ESC Guidelines

Guidelines on the management of stableangina pectoris: full text{

The Task Force on the Management of Stable Angina Pectoris ofthe European Society of Cardiology

Authors/Task Force Members, Kim Fox, Chairperson, London (UK)*, Maria Angeles Alonso Garcia,Madrid (Spain), Diego Ardissino, Parma (Italy), Pawel Buszman, Katowice (Poland), Paolo G. Camici,London (UK), Filippo Crea, Roma (Italy), Caroline Daly, London (UK), Guy De Backer, Ghent(Belgium), Paul Hjemdahl, Stockholm (Sweden), Jose Lopez-Sendon, Madrid (Spain), Jean Marco,Toulouse (France), Joao Morais, Leiria (Portugal), John Pepper, London (UK), Udo Sechtem,Stuttgart (Germany), Maarten Simoons, Rotterdam (The Netherlands), Kristian Thygesen, Aarhus(Denmark)

ESC Committee for Practice Guidelines (CPG), Silvia G. Priori (Chairperson) (Italy), Jean-Jacques Blanc (France),Andrzej Budaj (Poland), John Camm (UK), Veronica Dean (France), Jaap Deckers (The Netherlands), Kenneth Dickstein(Norway), John Lekakis (Greece), Keith McGregor (France), Marco Metra (Italy), Joao Morais (Portugal), Ady Osterspey(Germany), Juan Tamargo (Spain), Jose L. Zamorano (Spain)

Document Reviewers, Jose L. Zamorano (CPG Review Coordinator) (Spain), Felicita Andreotti (Italy), Harald Becher(UK), Rainer Dietz (Germany), Alan Fraser (UK), Huon Gray (UK), Rosa Ana Hernandez Antolin (Spain), Kurt Huber(Austria), Dimitris T. Kremastinos (Greece), Attilio Maseri (Italy), Hans-Joachim Nesser (Austria), Tomasz Pasierski(Poland), Ulrich Sigwart (Switzerland), Marco Tubaro (Italy), Michael Weis (Germany)

Table of Contents

Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . 2Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . 3Definition and pathophysiology . . . . . . . . . . . . . . . 3Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . 5Natural history and prognosis . . . . . . . . . . . . . . . . 5Diagnosis and assessment . . . . . . . . . . . . . . . . . . 6

Symptoms and signs . . . . . . . . . . . . . . . . . . . 6Laboratory tests . . . . . . . . . . . . . . . . . . . . 7Chest X-ray . . . . . . . . . . . . . . . . . . . . . . . 8

Non-invasive cardiac investigations . . . . . . . . . . 8Resting ECG . . . . . . . . . . . . . . . . . . . . . . 8ECG stress testing . . . . . . . . . . . . . . . . . . . 9Stress testing in combination with imaging . . . . 11

Echocardiography at rest . . . . . . . . . . . . . . 13Ambulatory ECG monitoring . . . . . . . . . . . . . 13Non-invasive techniques to assess coronarycalcification and coronary anatomy . . . . . . . . 14

Invasive techniques to assess coronary anatomy . . . 14Coronary arteriography . . . . . . . . . . . . . . . . 14Intravascular ultrasound . . . . . . . . . . . . . . . 14Invasive assessment of functional severity ofcoronary lesions . . . . . . . . . . . . . . . . . . . . 15

Risk stratification . . . . . . . . . . . . . . . . . . . . 15Risk stratification using clinical evaluation . . . . 16Risk stratification using stress testing . . . . . . . 19Risk stratification using ventricular function . . . 20Risk stratification using coronary arteriography . 22

& The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

y

* Corresponding author. Chairperson: Kim Fox, Department of Cardiology,Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. Tel: þ44 207351 8626; fax: þ44 207 351 8629.

E-mail address:k.fox@rbh.nthames.nhs.uk

{ CME questions for this article are available at European Heart Journalonline.‡ This is the full text version of Eur Heart J doi:10.1093/eurheartj/ehl001.

European Heart Journaldoi:10.1093/eurheartj/ehl002

The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized.No part of the ESC Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submissionof a written request to Oxford University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf ofthe ESC.Disclaimer. The ESC Guidelines represent the views of the ESC and were arrived at after careful consideration of the available evidence at the time they werewritten. Health professionals are encouraged to take them fully into account when exercising their clinical judgement. The guidelines do not, however, overridethe individual responsibility of health professionals to make appropriate decisions in the circumstances of the individual patients, in consultation with thatpatient, and where appropriate and necessary the patient’s guardian or carer. It is also the health professional’s responsibility to verify the rules andregulations applicable to drugs and devices at the time of prescription.

Special diagnostic considerations: anginawith ‘normal’ coronary arteries . . . . . . . . . . . . 22

Syndrome X . . . . . . . . . . . . . . . . . . . . . . 23Vasospastic/variant angina . . . . . . . . . . . . . . 24

Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . 25Aims of treatment . . . . . . . . . . . . . . . . . . . . 25General management . . . . . . . . . . . . . . . . . . 25

Treatment of the acute attack . . . . . . . . . . . 25Smoking . . . . . . . . . . . . . . . . . . . . . . . . 25Diet and alcohol . . . . . . . . . . . . . . . . . . . . 25Omega-3 fatty acids . . . . . . . . . . . . . . . . . 25Vitamins and antioxidants . . . . . . . . . . . . . . 26Hypertension, diabetes, and other disorders . . . 26Physical activity . . . . . . . . . . . . . . . . . . . . 26Psychological factors . . . . . . . . . . . . . . . . . 26Car driving . . . . . . . . . . . . . . . . . . . . . . . 26Sexual intercourse . . . . . . . . . . . . . . . . . . 26Employment . . . . . . . . . . . . . . . . . . . . . . 26

Pharmacological treatment of stable angina pectoris 26Pharmacological therapy to improve prognosis . . 27Pharmacological treatment of symptoms andischaemia . . . . . . . . . . . . . . . . . . . . . . . 34Special therapeutic considerations: cardiacSyndrome X and vasospastic angina . . . . . . . . 37

Myocardial revascularization . . . . . . . . . . . . . . 38Coronary artery bypass surgery . . . . . . . . . . . 38Percutaneous coronary intervention . . . . . . . . 39Revascularization vs. medical therapy . . . . . . . 39PCI vs. surgery . . . . . . . . . . . . . . . . . . . . . 40Specific patient and lesion subsets . . . . . . . . . 41Indications for revascularization . . . . . . . . . . 41Treatment of stable angina: multi-targetedtreatment of a multi-faceted disease . . . . . . . 43

Special subgroups . . . . . . . . . . . . . . . . . . . . 43Women . . . . . . . . . . . . . . . . . . . . . . . . . 43Diabetes mellitus . . . . . . . . . . . . . . . . . . . 44Elderly . . . . . . . . . . . . . . . . . . . . . . . . . 45Chronic refractory angina . . . . . . . . . . . . . . 45

Conclusions and Recommendations . . . . . . . . . . . . 46References . . . . . . . . . . . . . . . . . . . . . . . . . . 47

Preamble

Guidelines and Expert Consensus documents aim to presentmanagement recommendations based on all of the relevantevidence on a particular subject in order to help physiciansto select the best possible management strategies for theindividual patient, suffering from a specific condition,taking into account the impact on outcome and also therisk–benefit ratio of a particular diagnostic or therapeuticprocedure. Numerous studies have demonstrated thatpatient outcomes improvewhen guideline recommendations,basedon the rigorous assessment of evidence-based research,are applied in clinical practice.A great number of Guidelines and Expert Consensus

Documents have been issued in recent years by theEuropean Society of Cardiology (ESC) and also by other organ-izations or related societies. The profusion of documents canput at stake the authority and credibility of guidelines, par-ticularly if discrepancies appear between different docu-ments on the same issue, as this can lead to confusion in themind of physicians. In order to avoid these pitfalls, the ESC

and other organizations have issued recommendations for for-mulating and issuing Guidelines and Expert ConsensusDocuments. The ESC recommendations for guidelines pro-duction can be found on the ESC website (Recommendationsfor ESC Guidelines Production at www.escardio.org). It isbeyond the scope of this preamble to recall all but thebasic rules.

In brief, the ESC appoints experts in the field to carry outa comprehensive review of the literature, with a view tomaking a critical evaluation of the use of diagnostic andtherapeutic procedures and assessing the risk–benefit ratioof the therapies recommended for management and/orprevention of a given condition. Estimates of the expectedhealth outcomes are included, where data exist. Thestrength of evidence for or against particular proceduresor treatments is weighed, according to predefined scalesfor grading recommendations and levels of evidence, asoutlined subsequently.

The Task Force members of the writing panels, as well asthe document reviewers, are asked to provide disclosurestatements of all relationships they may have, which mightbe perceived as real or potential conflicts of interest.These disclosure forms are kept on file at the EuropeanHeart House, headquarters of the ESC, and can be madeavailable by written request to the ESC President. Anychanges in conflict of interest that arise during the writingperiod must be notified to the ESC.

Guidelines and recommendations are presented informats that are easy to interpret. They should helpphysicians to make clinical decisions in their daily routinepractice, by describing the range of generally acceptableapproaches to diagnosis and treatment. However, theultimate judgment regarding the care of individualpatients must be made by the physician in charge of theircare.

The ESC Committee for Practice Guidelines (CPG) super-vises and coordinates the preparation of new Guidelinesand Expert Consensus Documents produced by Task Forces,expert groups or consensus panels. The committee is alsoresponsible for the endorsement of these Guidelines andExpert Consensus Documents or statements.

Once the document has been finalized and approved by allthe experts involved in the Task Force, it is submitted tooutside specialists for review. In some cases, the documentcan be presented to a panel of key opinion leaders inEurope, specialists in the relevant condition at hand, for dis-cussion and critical review. If necessary, the document isrevised once more and, finally, approved by the CPG andselected members of the board of the ESC and subsequentlypublished.

After publication, dissemination of the message is of para-mount importance. Publication of executive summaries andthe production of pocket-sized and PDA-downloadable ver-sions of the recommendations are helpful. However,surveys have shown that the intended end-users are oftennot aware of the existence of guidelines or simply do notput them into practice. Implementation programmes arethus necessary and form an important component of the dis-semination of knowledge. Meetings are organized by the ESCand directed towards its member National Societies andkey opinion leaders in Europe. Implementation meetingscan also be undertaken at a national level, once theguidelines have been endorsed by the ESC member

2 ESC Guidelines

societies and translated into the local language, whennecessary.All in all, the task of writing Guidelines or Expert

Consensus Document covers not only the integration of themost recent research but also the creation of educationaltools and implementation programmes for the recommen-dations. The loop between clinical research, writing ofguidelines, and implementing them into clinical practicecan then only be completed if surveys and registries areorganized to verify that actual clinical practice is inkeeping with what is recommended in the guidelines. Suchsurveys and registries also make it possible to check theimpact of strict implementation of the guidelines onpatient outcome.

Classes of Recommendations

Introduction

Stable angina pectoris is a common and disabling disorder.However, the management of stable angina has not beensubjected to the same scrutiny by large randomized trialsas has, for example, that of acute coronary syndromes(ACS) including unstable angina and myocardial infarction(MI). The optimal strategy of investigation and treatmentis difficult to define, and the development of new tools forthe diagnostic and prognostic assessment of patients,along with the continually evolving evidence base forvarious treatment strategies, mandates that the existingguidelines be revised and updated. The Task Force hastherefore obtained opinions from a wide variety of expertsand has tried to achieve agreement on the best contempor-ary approaches to the care of stable angina pectoris, bearingin mind not only the efficacy and safety of treatments but

also the cost and the availability of resources. The TaskForce has taken the view that these guidelines shouldreflect the pathophysiology and management of angina pec-toris, namely myocardial ischaemia due to coronary arterydisease (CAD), usually macrovascular, i.e. involving largecoronary arteries, but also microvascular in some of thepatients. Furthermore, this Task Force does not deal withprimary prevention, which has already been covered inother recently published guidelines1 and has limited its dis-cussion on secondary prevention. Recently published guide-lines and consensus statements that overlap to aconsiderable extent with the remit of this document arelisted in Table 1.

Definition and pathophysiology

Stable angina is a clinical syndrome characterized bydiscomfort in the chest, jaw, shoulder, back, or arms, typi-cally elicited by exertion or emotional stress and relievedby rest or nitroglycerin. Less typically, discomfort mayoccur in the epigastric area. William Heberden first intro-duced the term ‘angina pectoris’ in 17722 to characterizea syndrome in which there was ‘a sense of strangling andanxiety’ in the chest, especially associated with exercise,although its pathological aetiology was not recognizeduntil some years later.3 It is now usual to confine theterm to cases in which the syndrome can be attributed tomyocardial ischaemia, although essentially similar symp-toms can be caused by disorders of the oesophagus,lungs, or chest wall. Although the most common cause ofmyocardial ischaemia is atherosclerotic CAD, demonstrablemyocardial ischaemia may be induced in the abscence byhypertrophic or dilated cardiomyopathy, aortic stenosis,or other rare cardiac conditions in the absence of obstruc-tive atheromatous coronary disease, which are notconsidered in this document.Myocardial ischaemia is caused by an imbalance between

myocardial oxygen supply and myocardial oxygen consump-tion. Myocardial oxygen supply is determined by arterialoxygen saturation and myocardial oxygen extraction,which are relatively fixed under normal circumstances,and coronary flow, which is dependent on the luminal cross-sectional area of the coronary artery and coronary arteriolartone. Both cross-sectional area and arterioloar tone may bedramatically altered by the presence of atheroscleroticplaque within the vessel wall, leading to imbalancebetween supply and demand when myocardial oxygendemands increase, as during exertion, related to increasesin heart rate, myocardial contractility, and wall stress.Ischaemia-induced sympathetic activation can furtherincrease the severity of ischaemia through a variety ofmechanisms including a further increase of myocardialoxygen consumption and coronary vasoconstriction. Theischaemic cascade is characterized by a sequence ofevents, resulting in metabolic abnormalities, perfusion mis-match, regional and then global diastolic and systolic dys-function, electrocardiographic (ECG) changes, and angina.Adenosine released by ischaemic myocardium appears tobe the main mediator of angina (chest pain) through stimu-lation of A1 receptors located on cardiac nerve endings.4

Ischaemia is followed by reversible contractile dysfunctionknown as ‘stunning’. Recurrent episodes of ischaemia and

Class I Evidence and/or general agreement that a givendiagnostic procedure/treatment is beneficial,useful, and effective

Class II Conflicting evidence and/or a divergence of opinionabout the usefulness/efficacy of the treatmentor procedure

Class IIa Weight of evidence/opinion is in favour ofusefulness/efficacy

Class IIb Usefulness/efficacy is less well established byevidence/opinion

Class III Evidence or general agreement that the treatmentor procedure is not useful/effective and, in somecases, may be harmful

Level of evidence A Data derived from multiple randomizedclinical trials or meta-analyses

Level of evidence B Data derived from a single randomizedclinical trial or large non-randomizedstudies

Level of evidence C Consensus of opinion of the experts and/orsmall studies, retrospective studies, andregistries

ESC Guidelines 3

stunning may lead to a chronic but still reversible form ofdysfunction known as ‘hibernation’. A brief episode ofischaemia results in ‘preconditioning’, a powerful endo-genous form of protection which makes the heart moreresistant to subsequent ischaemic episodes.5

Myocardial ischaemia may also be silent.6 Lack of painmay be due to ischaemia of insufficient duration and/orseverity, to damage of afferent cardiac nerves, or to inhi-bition of ischaemic cardiac pain at spinal or supraspinallevel. In patients who exhibit painless ischaemia, shortnessof breath, and palpitation may represent anginal equiva-lents. Breathlessness may be due to ischaemic left ventricu-lar (LV) systolic or diastolic dysfunction or to transientischaemic mitral regurgitation.In the majority of patients, the pathological substrate of

stable angina is atheromatous, narrowing of the coronaryarteries. The normal vascular bed has the capacity toreduce resistance such that coronary blood flow increasesby up to 5–6-fold during maximal exercise. Reduction inthe luminal cross-sectional area by atheroscleroticplaque reduces the normal ability of the coronary vascularbed to reduce its resistance during maximal exercise withresultant ischaemia dependent on the degree of obstruc-tion and myocardial oxygen demands. When luminalobstruction is �40% maximal flow during exercise canusually be maintained. But luminal diameter reduction of.50% may be associated with ischaemia when coronary

blood flow becomes inadequate to meet cardiac metabolicdemand during exercise or stress.7,8 Stenosis resistancechanges relatively little with mild degrees of vascular nar-rowing but rises precipitously with severe obstruction,with resistance almost tripling between stenosis of 80%and 90%. For a similar degree of stenosis, the ischaemicthreshold is influenced by other factors including thedegree of development of collateral circulation, thedegree of transmural distribution of myocardial perfusionfrom the more vulnerable subendocardium to the subepi-cardium, coronary vascular tone, and platelet aggregation.Endothelial dysfunction as a cause of angina is discussed inSyndrome X. Rarely, angina may be caused by myocardialbridging.9

In stable angina, the angina threshold may vary consider-ably from day to day and even during the same day.Symptom variability is due to a variable degree of vasocons-triction at the site of critical stenoses (dynamic stenoses)and/or distal coronary vessels, depending on factors suchas ambient temperature, mental stress, and neuro-hormonalinfluences.10 In a sizeable proportion of patients, anginamay occasionally occur even at rest.

Patients with stable angina are at risk of developing an ACS:unstable angina, non-ST-elevation MI or ST-elevation MI.Unstable angina is characterized by a sudden worsening ofangina symptoms, which become more frequent, more pro-longed, and more severe and/or occur at a lower threshold

Table 1 Recently published Guidelines and Consensus Statements that overlap with this guideline

Guideline Developed by Year of publication

European Guidelines on PCI in clinical practice ESC 2005587

ACC/AHA Guideline Update for CoronaryArtery Bypass Graft Surgery

ACC/AHA 2004614

Expert Consensus Document on angiotensinenzyme inhibitors in CVD

ESC 2004676

Expert Consensus Document on b-adrenergic receptor blockers ESC 2004677

Imaging techniques to detect myocardial hibernation.A report by the ESC Working Group

ESC 2004199

Expert Consensus Document on the use of antiplatelet agents ESC 2004384

Evidence-based Guidelines for Cardiovascular DiseasePrevention in Women

AHA, ACC, ACNP, ACOG, ACP, AMWA, ABC,CDCP, NHLBI, ORWH, STS, and WHF

2004349

European guidelines on CVD prevention in clinical practice(Third Joint Task Force report)

ESC and other societies 20031

ACC/AHA/ASE Guideline Update for the Clinical Applicationof Echocardiography

ACC/AHA/ASE 2003155

Consensus Statement American Society of Nuclear Cardiology:Task Force Report on Women and CAD. The role of myocardialperfusion imaging in the clinical evaluation of CAD in women

Am. Coll. of Nuclear Cardiology 2003678

ACC/AHA Guideline Update for Exercise Testing ACC/AHA 2002140

ACC/AHA Guideline Update for the Management of Patients withChronic Stable Angina

ACC/AHA 2002379

ACC Clinical Expert Consensus Document on Standards forAcquisition, Measurement and Reporting of IntravascularUltrasound Studies (IVUS)

ACC/ESC 2001246

American College of Cardiology/American Heart AssociationExpert Consensus Document on Electron Beam ComputedTomography for the Diagnosis and Prognosis of CAD

ACC/AHA 2000234

ACC/AHA Guidelines for Coronary Arteriography ACC/AHA 1999679

Management of stable angina pectoris. Recommendations of theTask Force of the European Society of Cardiology

ESC 1997680

ESC Working Group on Exercise Physiology, Physiopathology,and Electrocardiography. Guidelines for Cardiac Exercise Testing

ESC 1993135

4 ESC Guidelines

or at rest.11 MI is characterized by prolonged angina(.30 min) associated with myocardial necrosis.12 Bothnon-ST-elevation and ST-elevation MI are frequently pre-ceded by a period of days, or even weeks, of unstable symp-toms. The common pathological background of ACS is erosion,fissure, or rupture of an atherosclerotic coronary plaqueassociated with platelet aggregation, leading to subtotal ortotal thrombotic coronary occlusion. Activated plateletsrelease a number of vasoconstrictors, which may furtherimpair coronary flow through the stimulation of vascularsmooth muscle cells both locally and distally. The haemo-dynamic severity of the atherosclerotic plaque prior to desta-bilization is frequently mild and the plaques are lipid filledwith foam cells. Intravascular ultrasound studies haveshown that so-called vulnerable plaques (i.e. at risk of caprupture) that are ,50% in diameter both precede andpredict future acute syndromes occurring precisely in theirneighbourhood.13 Activation of inflammatory cells withinthe atherosclerotic plaque appears to play an importantrole in the destabilization process,14 leading to plaqueerosion, fissure, or rupture. More recently, the concept of asingle vulnerable plaque causing an ACS has been challengedin favour of a more generalized inflammatory response.15

Epidemiology

As angina is essentially a diagnosis based on history, andtherefore subjective, it is understandable that its preva-lence and incidence have been difficult to assess and mayvary between studies dependent on the definition that hasbeen used.For epidemiological purposes, the London School of

Hygiene and Tropical Medicine cardiovascular questionnaire,devised by Rose and Blackburn16 and adopted by the WHO,has been widely used. It defines angina as chest pain,pressure, or heaviness that limits exertion, is situated overthe sternum or in the left chest and left arm, and is relievedwithin 10 min of rest. The questionnaire allows a subdivisionof symptoms into definite and possible angina, which can befurther subdivided into grade 1 and grade 2.17 It should berecognized that this questionnaire is a screening tool andnot a diagnostic test.Rose angina questionnaire predicts cardiovascularmorbidity

and mortality in European18,19 and American populations,20

independent of other risk factors. Therefore, it has beenindirectly validated. It has been compared with otherstandards including a clinical diagnosis,21 ECG findings,22

radionuclide tests,23 and coronary arteriography.24 On thebasis of such comparisons, its specificity is �80–95% but itssensitivity varies greatly from 20 to 80%. The exertionalcomponent of the symptoms is crucial to the diagnosticaccuracy of the questionaire,18 and its performance seemsto be less accurate in women.25

The prevalence of angina in community studies increasessharply with age in both sexes from 0.1–1% in women aged45–54 to 10–15% in women aged 65–74 and from 2–5% inmen aged 45–54 to 10–20% in men aged 65–74.26–33

Therefore, it can be estimated that in most Europeancountries, 20 000–40 000 individuals of the population permillion suffer from angina.Community-based information on the incidence of angina

pectoris is derived from prospective, epidemiologic studieswith repeated examinations of the cohort. Such studies

have been scarce over recent years. Available data, fromthe Seven Countries study,34 studies in the UK,35,36 theIsrael Ischaemic Heart Disease study,37 the Honolulu Heartstudy,38 the Framingham study39,40 and others,41 suggestan annual incidence of uncomplicated angina pectorisof �0.5% in western populations aged .40, but withgeographic variations evident.A more recent study, using a different definition of angina

based on case description by clinicians, which definedangina pectoris as the association of chest pain at rest oron exertion with one positive finding from a cardiovascularexamination such as arteriography, scintigraphy, exercisetesting, or resting ECG,42 confirm geographical variationsin the incidence of angina which occur in parallel withobserved international differences in coronary heartdisease (CHD) mortality. The incidence of angina pectorisas a first coronary event was approximately twice high inBelfast compared with France (5.4 per 1000 person-yearscompared with 2.6).Temporal trends suggest a decrease in the prevalence of

angina pectoris in recent decades35,43 in line with falling car-diovascular mortality rates observed in the MONICA44 study.However, the prevalence of a history of diagnosed CHD doesnot appear to have decreased, suggesting that althoughfewer people are developing angina due to changes in life-style and risk factors, those who have coronary disease areliving longer with the disease. Improved sensitivity of diag-nostic tools may additionally contribute to the contemporaryhigh prevalence of diagnosed CHD.

Natural history and prognosis

Information on the prognosis associated with chronic stableangina is derived from long-term prospective, population-based studies, clinical trials of antianginal therapy, andobservational registries, with selection bias an importantfactor to consider when evaluating and comparing the avail-able data. European data estimate the cardiovasculardisease (CVD) mortality rate and CHD mortality rates formen with Rose questionnaire angina to be between 2.6and 17.6 per 1000 patient-years between the 1970s and1990s.35,45 Data from the Framingham Heart Study40,46

showed that for men and women with an initial clinical pres-entation of stable angina, the 2-year incidence rates of non-fatal MI and CHD death were 14.3 and 5.5% in men and 6.2and 3.8% in women, respectively. More contemporary dataregarding prognosis can be gleaned from clinical trials ofantianginal therapy and/or revascularization, althoughthese data are biased by the selected nature of the popu-lations studied. From these, estimates for annual mortalityrates range from 0.9–1.4% per annum,47–51 with an annualincidence of non-fatal MI between 0.5% (INVEST)50 and2.6% (TIBET).48 These estimates are consistent with observa-tional registry data.52

However, within the population with stable angina, anindividual’s prognosis can vary considerably, by up to10-fold, dependent on baseline clinical, functional, and ana-tomical factors. Therefore, prognostic assessment is animportant part of the management of patients with stableangina. On the one hand, it is important to carefullyselect those patients with more severe forms of diseaseand candidates for revascularization and potential

ESC Guidelines 5

improvement in outcome with more aggressive investigationand treatment. On the other hand, it is also important toselect those patients with a less severe form of disease,with a good outcome, thereby avoiding unnecessary invasiveand non-invasive tests and procedures.Conventional risk factors for the development of

CAD,26,53–55,56 hypertension, hypercholesterolaemia56–59

diabetes,60–65 and smoking26 have an adverse influence onprognosis in those with established disease, presumablythrough their effect on disease progression. However, appro-priate treatment can reduce or abolish these risks. Otherfactors predictive of long-term prognosis of patients withstable angina have been determined from the follow-up ofthe large control groups of randomized trials aimed at eval-uating the effectiveness of revascularization66,67 and otherobservational data. In general, the outcome is worse inpatients with reduced LV function, a greater number ofdiseased vessels, more proximal locations of coronarystenosis, greater severity of lesions, more severe angina,more extensive ischaemia, and greater age.LV function is the strongest predictor of survival in

patients with chronic stable coronary disease; the nextmost important factor is the distribution and severity ofcoronary stenosis. Left main (LM) disease, three-vesseldisease, and the proximal involvement of the left anteriordescending are common characteristics predicting a pooroutcome and increase the risk of ischaemic events.68

Myocardial revascularization can reduce the risk of deathin selected anatomical subgroups,69 reduce the number ofischaemic episodes (ACIP),70 and in some instances mayimprove the LV function in high-risk patients.71,72 However,disease progression and the occurrence of acute eventsmay not necessarily be related to the severity of stenosisat coronary arteriography. In all patients, smaller lipidfilled plaques are present in addition to those that causesevere stenoses. As discussed earlier, these ‘vulnerableplaques’ have a greater likelihood to rupture.14 Thus,the risk of acute events is related to the overall plaqueburden and to plaque vulnerability. Although an areaof great research interest, our capabilities to identifyvulnerable plaque remain limited.

Diagnosis and assessment

Diagnosis and assessment of angina involves clinical asses-sment, laboratory tests, and specific cardiac investigations.Clinical assessment related to diagnosis and basic laboratoryinvestigations are dealt with in this section. Cardiac specificinvestigations may be non-invasive or invasive and may beused to confirm the diagnosis of ischaemia in patients withsuspected stable angina, to identify or exclude associatedconditions or precipitating factors, for risk stratification,and to evaluate the efficacy of treatment. Some should beused routinely in all patients; others provide redundantinformation except in particular circumstances; someshould be easily available to cardiologists and generalphysicians, yet others may be considered as tools forresearch. In practice, diagnostic and prognostic assessmentsare conducted in tandem rather than separately, and manyof the investigations used for diagnosis also offer prognosticinformation. For the purposes of description and presen-tation of the evidence, the individual investigative tech-niques are discussed subsequently with recommendations

for diagnosis. Specific cardiac investigations routinely usedfor risk stratification purposes are discussed separately inthe following section.

Symptoms and signs

A careful history remains the cornerstone of the diagnosis ofangina pectoris. In the majority of cases, it is possible tomake a confident diagnosis on the basis of the historyalone, although physical examination and objective testsare necessary to confirm the diagnosis and assess theseverity of underlying disease.

The characteristics of discomfort related to myocardialischaemia (angina pectoris) have been extensively describedand may be divided into four categories, location, character,duration, and relation to exertion and other exacerbating orrelieving factors. The discomfort caused by myocardialischaemia is usually located in the chest, near thesternum, but may be felt anywhere from the epigastriumto the lower jaw or teeth, between the shoulder blades orin either arm to the wrist and fingers. The discomfort isusually described as pressure, tightness, or heaviness, some-times strangling, constricting, or burning. The severity ofthe discomfort varies greatly and is not related to the sever-ity of the underlying coronary disease. Shortness of breathmay accompany angina, and chest discomfort may be alsobe accompanied by less specific symptoms such as fatigueor faintness, nausea, burping, restlessness, or a sense ofimpending doom.

The duration of the discomfort is brief, nomore than 10 minin the majority of cases, and more commonly even minutesless. An important characteristic is the relation to exercise,specific activities, or emotional stress. Symptoms classicallydeteriorate with increased levels of exertion, such aswalking up an incline, or against a breeze and rapidly disap-pear within a few minutes, when these causal factors abate.Exacerbations of symptoms after a heavy meal or first thingin the morning are classical features of angina. Buccal or sub-lingual nitrates rapidly relieve angina, and a similar rapidresponse may be observed with chewing nifedipine capsules.

Non-anginal pain lacks the characteristic qualitiesdescribed, may involve only a small portion of the left hemi-thorax, and last for several hours or even days. It is usuallynot relieved by nitroglycerin (although it may be in the caseof oesophageal spasm) and may be provoked by palpation.Noncardiac causes of pain should be evaluated in such cases.

Definitions of typical and atypical angina have beenpreviously published,73 summarized on Table 2. It is

Table 2 Clinical classification of chest pain

Typical angina (definite) Meets three of the followingcharacteristics† Substernal chest discomfort ofcharacteristic qualityand duration

† Provoked by exertion oremotional stress

† Relieved by rest and/or GTNAtypical angina (probable) Meets two of these characteristicsNon-cardiac chest pain Meets one or none of

the characteristics

6 ESC Guidelines

important when taking the history to identify those patientswith unstable angina, which may be associated with plaquerupture, who are at significantly higher risk of an acutecoronary event in the short-term. Unstable angina maypresent in one of the three ways: (i) as rest angina, i.e.pain of characteristic nature and location, but occurring atrest and for prolonged periods, up to 20 min; (ii) rapidlyincreasing or crescendo angina, i.e. previously stableangina, which progressively increases in severity and inten-sity and at lower threshold over a short period, 4 weeks orless; or (iii) new onset angina, i.e. recent onset of severeangina, such that the patient experiences marked limitationof ordinary activity within 2 months of initial presentation.The investigation and management of suspected unstableangina is dealt with in guidelines for the management of ACS.For patients with stable angina, it is also useful to classify

the severity of symptoms using a grading system such as thatof the Canadian Cardiovascular Society Classification(Table 3). This is useful in determining the functional impair-ment of the patient and quantifying response to therapy.The Canadian Cardiovascular Society Classification74 iswidely used as a grading system for angina to quantify thethreshold at which symptoms occur in relation to physicalactivities. Alternative classification systems such as DukeSpecific Activity Index75 and Seattle angina questionnaire76

may also be used in determining the functional impairmentof the patient and quantifying response to therapy and mayoffer superior prognostic capability.77

Physical examination of a patient with (suspected) anginapectoris is important to assess the presence of hypertension,valvular heart disease, or hypertrophic obstructive cardio-myopathy. Physical examination should include assessmentof body-mass index (BMI) and waist circumference to assistevaluation of the metabolic syndrome,78,79 evidence ofnon-coronary vascular disease which may be asymptomatic,and other signs of comorbid conditions. However, there areno specific signs in angina pectoris. During or immediatelyafter an episode of myocardial ischaemia, a third or fourthheart sound may be heard and mitral insufficiency mayalso be apparent during ischaemia. Such signs are,however, elusive and non-specific.

Laboratory testsLaboratory investigations may be loosely grouped into thosethat provide information related to possible causes ofischaemia, those that may be used to establish cardiovascu-lar risk factors and associated conditions, and those thatmay be used to determine prognosis. Some laboratory inves-tigations are used for more than one of these purposes andmay be applied routinely in all patients, whereas otherinvestigations should be reserved for use where clinicalhistory and/or examination indicates a particular need fortheir application.Haemoglobin and, where there is clinical suspicion of a

thyroid disorder, thyroid hormones provide informationrelated to possible causes of ischaemia. The full bloodcount incorporating total white cell count as well as haemo-globin may also add prognostic information.80 If there isclinical suspicion of instability, biochemical markers of myo-cardial damage such as troponin or CKMB (creatine kinasemyocardial band), measured by mass assay, should beemployed to exclude myocardial injury. If these markersare elevated, management should continue as for an ACSrather than stable angina. After initial assessment, thesetests are not recommended as routine investigationsduring each subsequent evaluation.Fasting plasma glucose60,61,63,64,81,82,83,84 and fasting lipid

profile including total cholesterol (TC), high density lipo-protein (HDL) cholesterol, and low density lipoprotein(LDL) cholesterol,55–58 and triglycerides54,85 should be eval-uated in all patients with suspected ischaemic disease,including stable angina, to establish the patient’s riskprofile and ascertain the need for treatment. Lipid profileand glycaemic status should be re-assessed periodically todetermine efficacy of treatment and in non-diabeticpatients to detect new development of diabetes. There isno evidence to support recommendations for how regularlyreassessment should take place. Consensus suggests annualmeasurement. Patients with very high levels of lipids, inwhom the progress of any intervention needs to be moni-tored, should have measurements more frequently.Patients with diabetes should be managed accordingly.Serum creatinine is a simple but crude method to evaluate

renal function. Renal dysfunction may occur due to asso-ciated comorbidity86–91 such as hypertension, diabetes orrenovascular disease and has a negative impact on prognosisin patients with CVD,92,93 giving good grounds for measure-ment at initial evaluation in all patients with suspectedangina. The Cockcroft–Gault formula94 may be used toestimate creatinine clearance based on age, sex, weight,and serum creatinine. The commonly used formula is asfollows: ((140—age (years)) � (actual weight (kg)))/(72 �

serum creatinine (mg/dL)), with multiplication by a factorof 0.85 if female.In addition to the well-recognized association between

adverse cardiovascular outcome and diabetes, elevationsof fasting or post-glucose challenge glycaemia have alsobeen shown to predict adverse outcome in stable coronarydisease independently of conventional risk factors.95–101

Although HbAIc predicts outcome in the general population,there is less data in those with CAD.101,102 Obesity, and inparticular evidence of the metabolic syndrome, is predictiveof adverse cardiovascular outcome in patients with estab-lished disease as well as asymptomatic populations.78,79,103

The presence of the metabolic syndrome can be determined

Table 3 Classification of angina severity according to theCanadian Cardiovascular Society

Class Level of symptoms

Class I ‘Ordinary activity does not cause angina’Angina with strenuous or rapid

or prolonged exertion onlyClass II ‘Slight limitation of ordinary activity’

Angina on walking or climbing stairs rapidly,walking uphill or exertion after meals, incold weather, when under emotional stress,or only during the first few hours after awakening

Class III ‘Marked limitation of ordinary physical activity’Angina on walking one or two blocksa on the level

or one flight of stairs at a normal pace undernormal conditions

Class IV ‘Inability to carry out any physical activitywithout discomfort’ or ‘angina at rest’

aEquivalent to 100–200 m.

ESC Guidelines 7

from assessment of waist circumference (or BMI), bloodpressure, HDL, triglycerides, and fasting glucose levelsand offers additional prognostic information to thatobtained from conventional Framingham risk scores104

without major additional cost in terms of laboratoryinvestigation.Further laboratory testing, including cholesterol subfrac-

tions (ApoA and ApoB)105,106 homocysteine,107,108 lipoprotein(a) (Lpa), haemostatic abnormalities,109–112 and markers ofinflammation such as hs-C-reactive protein,56,113,114 havebeen the subject of much interest as methods to improvecurrent risk prediction.113,115 However, markers of inflam-mation fluctuate over time and may not be a reliable esti-mator of risk in the longer term.116 More recently, NT-BNPhas been shown to be an important predictor of long-termmortality independent of age, ventricular ejection fraction(EF), and conventional risk factors.117 As yet, there isinadequate information regarding how modification ofthese biochemical indices can significantly improve oncurrent treatment strategies to recommend their use in allpatients, particularly given the constraints of cost and avail-ability. Nevertheless, these measurements have a role inselected patients, for example, testing for haemostaticabnormalities in those with prior MI without conventionalrisk factors,118 or a strong family history of coronarydisease, or where resources are not limited. Furtherresearch into their use is welcomed. The use of glycatedhaemoglobin or response to oral glucose load in additionto a single measurement of fasting plasma glucose havealso been shown to improve detection of glycaemic abnorm-alities, but as yet there is insufficient evidence to rec-ommend this strategy in all patients with chest pain.119,120

This may be a useful method of detecting glycaemicabnormalities in selected patients particularly at high riskfor their development.Recommendations for laboratory investigation in initial

assessment of stable anginaClass I (in all patients)

(1) Fasting lipid profile, including TC, LDL, HDL, andtriglycerides (level of evidence B)

(2) Fasting glucose (level of evidence B)(3) Full blood count including Hb and white cell count

(level of evidence B)(4) Creatinine (level of evidence C)

Class I (if specifically indicated on the basis of clinicalevaluation)

(1) Markers of myocardial damage if evaluation suggestsclinical instability or ACS (level of evidence A)

(2) Thyroid function if clinically indicated (level ofevidence C)

Class IIa

(1) Oral glucose tolerance test (level of evidence B)

Class IIb

(1) Hs-C-reactive protein (level of evidence B)(2) Lipoprotein a, ApoA, and ApoB (level of evidence B)(3) Homocysteine (level of evidence B)(4) HbA1c (level of evidence B)(5) NT-BNP (level of evidence B)

Recommendations for blood tests for routinereassessment in patients with chronic stable anginaClass IIa

(1) Fasting lipid profile and fasting glucose on an annualbasis (level of evidence C)

Chest X-rayA chest X-ray (CXR) is frequently used in the assessmentof patients with suspected heart disease. However, instable angina, the CXR does not provide specific informationfor diagnosis or risk stratification. The test should berequested only in patients with suspected heartfailure,121,122 valvular disease, or pulmonary disease.Thepresence of cardiomegaly, pulmonary congestion, atrialenlargement, and cardiac calcifications has been relatedto impaired prognosis.123–128

Recommendations for CXR for initial diagnosticassessment of anginaClass I

(1) CXR in patients with suspected heart failure (level ofevidence C)

(2) CXR in patients with clinical evidence of significantpulmonary disease (level of evidence B)

Non-invasive cardiac investigations

This section will describe investigations used in the asses-sment of angina and concentrate on recommendations fortheir use in diagnosis and evaluation of efficacy oftreatment, and recommendations for risk stratification willbe dealt with in the following section. As there are few ran-domized trials assessing health outcomes for diagnostictests, the available evidence has been ranked according toevidence from non-randomized studies or meta-analyses ofthese studies.

Resting ECGAll patients with suspected angina pectoris based on symp-toms should have a resting 12-lead ECG recorded. It shouldbe emphasized that a normal resting ECG is not uncommoneven in patients with severe angina and does not excludethe diagnosis of ischaemia. However, the resting ECG mayshow signs of CAD such as previous MI or an abnormalrepolarization pattern. The ECG may assist in clarifyingthe differential diagnosis if taken in the presence of pain,allowing detection of dynamic ST-segment changes inthe presence of ischaemia,129,130 or by identifying featuresof pericardial disease. An ECG during pain may beparticularly useful if vasospasm is suspected. The ECG mayalso show other abnormalities such as left ventricularhypertrophy (LVH), left bundle branch block (LBBB),pre-excitation, arrhythmias, or conduction defects.Such information may be helpful in defining themechanisms responsible for chest pain, in selectingappropriate further investigation, or in tailoring individualpatient treatment. The resting ECG also has an impor-tant role in risk stratification, as outlined in the RiskStratification section.131–133

There is little direct evidence to support routinely repeat-ing the resting ECG at frequent intervals unless to obtain anECG during pain or if there has been a change in functionalclass.

8 ESC Guidelines

Recommendations for resting ECG for initial diagnosticassessment of anginaClass I (in all patients)

(1) Resting ECG while pain free (level of evidence C)(2) Resting ECG during episode of pain (if possible) (level of

evidence B)

Recommendations for resting ECG for routine reassess-ment in patients with chronic stable anginaClass IIb

(1) Routine periodic ECG in the absence of clinical change(level of evidence C)

ECG stress testingExercise ECG is more sensitive and specific than the restingECG for detecting myocardial ischaemia134,135 and forreasons of availability and cost is the test of choice to identifyinducible ischaemia in the majority of patients withsuspected stable angina. There are numerous reportsand meta-analyses of the performance of exercise ECGfor the diagnosis of coronary disease.136–139 Using exerciseST-depression ,0.1 mV or 1 mm to define a positive test,the reported sensitivity and specificity for the detection ofsignificant coronary disease range between 23–100% (mean68%) and 17–100% (mean 77%), respectively. Excludingpatients with prior MI, the mean sensitivity was 67% andspecificity 72%, and restricting analysis to those studiesdesigned to avoid work-up bias, sensitivity was 50% and speci-ficity 90%.140 The majority of reports are of studies where thepopulation tested did not have significant ECG abnormalitiesat baseline and were not on antianginal therapy or were with-drawn from antianginal therapy for the purposes of the test.Exercise ECG testing is not of diagnostic value in the presenceof LBBB, paced rhythm, and Wolff–Parkinson–White (WPW)syndrome, in which cases, the ECG changes cannot be evalu-ated. Additionally, false-positive results are more frequent inpatients with abnormal resting ECG in the presence of LVH,electrolyte imbalance, intraventricular conduction abnormal-ities, and use of digitalis. Exercise ECG testing is also less sen-sitive and specific in women.141

Interpretation of exercise ECG findings requires a Bayesianapproach to diagnosis. This approach uses clinicians’pre-test estimates of disease along with the results of diag-nostic tests to generate individualized post-test diseaseprobabilities for a given patient. The pre-test probabilityis influenced by the prevalence of the disease in the popu-lation studied, as well as clinical features in an individual.142

Therefore, for the detection of coronary disease, thepre-test probability is influenced by age and gender andfurther modified by the nature of symptoms at an individualpatient level before the results of exercise testing are usedto determine the posterior or post-test probability, asoutlined in Table 4.In populations with a low prevalence of ischaemic heart

disease the proportion of false-positive tests will be highwhen compared with a population with a high pre test prob-ability of disease. Conversely, in male patients with severeeffort angina, with clear ECG changes during pain, thepretest probability of significant coronary disease is high(.90%), and in such cases, the exercise test will not offeradditional information for the diagnosis, although it mayadd prognostic information.

A further factor that may influence the performance ofthe exercise ECG as a diagnostic tool is the definition of apositive test. ECG changes associated with myocardialischaemia include horizontal or down-sloping ST-segmentdepression or elevation [�1 mm (0.1 mV) for �60–80 msafter the end of the QRS complex], especially when thesechanges are accompanied by chest pain suggestive ofangina, occur at a low workload during the early stages ofexercise and persist for more than 3 min after exercise.Increasing the threshold for a positive test, for example,to �2 mm (0.2 mV) ST-depression, will increase specificityat the expense of sensitivity. A fall in systolic pressure orlack of increase of blood pressure during exercise and theappearance of a systolic murmur of mitral regurgitation orventricular arrhythmias during exercise reflect impaired LVfunction and increase the probability of severe myocardialischaemia and severe CAD. In assessing the significance ofthe test, not only the ECG changes but also the workload,heart rate increase and blood pressure response, heartrate recovery after exercise, and the clinical contextshould be considered.143 It has been suggested that evaluat-ing ST changes in relation to heart rate improves reliabilityof diagnosis144 but this may not be so in symptomaticpopulations.145–147

An exercise test should be carried out only after carefulclinical evaluation of symptoms and a physical examinationincluding resting ECG.135,140 Complications during exercisetesting are few but severe arrhythmias and even suddendeath can occur. Death and MI occur at a rate of less thanor equal to one per 2500 tests.148 Accordingly, exercisetesting should only be performed under careful monitoringin the appropriate setting. A physician should be presentor immediately available to monitor the test. The ECGshould be continuously recorded with a printout at pre-selected intervals, mostly at each minute during exercise,and 2–10 min of recovery after exercise. Exercise ECGshould not be carried out routinely in patients with knownsevere aortic stenosis or hypertrophic cardiomyopathy,although carefully supervised exercise testing may be usedto assess functional capacity in selected individuals withthese conditions.Either the Bruce protocol or one of its modifications on a

treadmill or a bicycle ergometer can be employed. Mostconsist of several stages of exercise, increasing in intensity,either speed, slope, or resistance or a combination of thesefactors, at fixed intervals, to test functional capacity. It isconvenient to express oxygen uptake in multiples ofresting requirements. One metabolic equivalent (MET) is aunit of sitting/resting oxygen uptake [3.5 mL of O2 per kilo-gram of body weight per minute (mL/kg/min)].149 Bicycleworkload is frequently described in terms of watts (W).Increments are of 20 W per 1 min stage starting from 20 to50 W, but increments may be reduced to 10 W per stage inpatients with heart failure or severe angina. Correlationbetween METs achieved and workload in watts varies withnumerous patient-specific and environmental factors.135,150

The reason for stopping the test and the symptoms at thattime, including their severity, should be recorded. Time tothe onset of ECG changes and/or symptoms, the overallexercise time, the blood pressure and heart rate response,the extent and severity of ECG changes, and the post-exercise recovery rate of ECG changes and heart rateshould also be assessed. For repeated exercise tests, the

ESC Guidelines 9

use of the Borg scale or similar method of quantifyingsymptoms may be used to allow comparisons.151 Reasonsto terminate an exercise test are listed in Table 5.In some patients, the exercise ECG may be non-

conclusive, for example, if at least 85% of maximum heartrate is not achieved in the absence of symptoms or ischae-mia, if exercise is limited by orthopaedic or other non-cardiac problems, or if ECG changes are equivocal. Unlessthe patient has a very low pre-test probability (,10% prob-ability) of disease, an inconclusive exercise test should befollowed by an alternative non-invasive diagnostic test.Furthermore, a ’normal’ test in patients taking anti-ischaemic drugs does not rule out significant coronarydisease.135 For diagnostic purposes, the test should be con-ducted in patients not taking anti-ischaemic drugs, althoughthis may not always be possible or considered safe.Exercise stress testing can also be useful for prognostic

stratification,152 to evaluate the efficacy of treatmentafter control of angina with medical treatment or revas-cularization or to assist prescription of exercise after

control of symptoms, but the effect of routine periodicalexercise testing on patient outcomes has not been formallyevaluated.

Recommendations for exercise ECG for initialdiagnostic assessment of anginaClass I

(1) Patients with symptoms of angina and intermediatepre-test probability of coronary disease based on age,gender, and symptoms, unless unable to exercise or dis-plays ECG changes which make ECG non-evaluable(level of evidence B)

Class IIb

(1) Patients with �1 mm ST-depression on resting ECG ortaking digoxin (level of evidence B)

(2) In patients with low pre-test probability (,10% prob-ability) of coronary disease based on age, gender, andsymptoms (level of evidence B)

Table 4 Probability of coronary disease in symptomatic patients based on (a) age, gender, and symptom classification and (b) modified byexercise test results

(a) Pretest likelihood of CAD in symptomatic patients according to age and sex

Age (years) Typical angina Atypical angina Non-anginal chest pain

Male Female Male Female Male Female

30–39 69.7+ 3.2 25.8+ 6.6 21.8+ 2.4 4.2+ 1.3 5.2+ 0.8 0.8+ 0.340–49 87.3+ 1.0 55.2+ 6.5 46.1+ 1.8 13.3+ 2.9 14.1+ 1.3 2.8+ 0.750–59 92.0+ 0.6 79.4+ 2.4 58.9+ 1.5 32.4+ 3.0 21.5+ 1.7 8.4+ 1.260–69 94.3+ 0.4 90.1+ 1.0 67.1+ 1.3 54.4+ 2.4 28.1+ 1.9 18.6+ 1.9

(b) CAD post-test likelihood (%) based on age, sex, symptom classification and exercise-induced electrocardiographicST-segment depression

Age (years) ST-depression (mV) Typical angina Atypical angina Non-anginal chest pain Asymptomatic

Male Female Male Female Male Female Male Female

30–39 0.00–0.04 25 7 6 1 1 ,1 ,1 ,10.05–0.09 68 24 21 4 5 1 2 40.00–0.14 83 42 38 9 10 2 4 ,10.00–0.19 91 59 55 15 19 3 7 10.00–0.24 96 79 76 33 39 8 18 3

.0.25 99 93 92 63 68 24 43 1140–49 0.00–0.04 61 22 16 3 4 1 1 ,1

0.00–0.09 86 53 44 12 13 3 5 10.00–0.14 94 72 64 25 26 6 11 20.00–0.19 97 84 78 39 41 11 20 40.00–0.24 99 93 91 63 65 24 39 10

.0.25 .99 98 97 86 87 53 69 2850–59 0.00–0.04 73 47 25 10 6 2 2 1

0.00–0.09 91 78 57 31 20 8 9 30.00–0.14 96 89 75 50 37 16 19 70.00–0.19 98 94 86 67 53 28 31 120.00–0.24 99 98 94 84 75 50 54 27

.0.25 .99 99 98 95 91 78 81 5660–69 0.00–0.04 79 69 32 21 8 5 3 2

0.00–0.09 94 90 65 52 26 17 11 70.00–0.14 97 95 81 72 45 33 23 150.00–0.19 99 98 89 83 62 49 37 250.00–0.24 99 99 96 93 81 72 61 47

.0.25 .99 99 99 98 94 90 85 76

10 ESC Guidelines

Recommendations for exercise ECG for routinere-assessment in patients with chronic stable anginaClass IIb

(1) Routine periodic exercise ECG in the absence of clinicalchange (level of evidence C)

Stress testing in combination with imagingThe most well established stress imaging techniques areechocardiography and perfusion scintigraphy. Both may beused in combination with either exercise stress or pharma-cological stress, and many studies have been conductedevaluating their use in both prognostic and diagnosticassessment over the past two decades or more. Novelstress imaging techniques also include stress MRI, which,for logistical reasons, is most frequently performed usingpharmacological rather than exercise stress.Stress imaging techniques have several advantages over

conventional exercise ECG testing including superior diag-nostic performance (Table 6) for the detection of obstruc-tive coronary disease, the ability to quantify and localizeareas of ischaemia, and the ability to provide diagnosticinformation in the presence of resting ECG abnormalitiesor inability of the patient to exercise. Stress imaging tech-niques are often preferred in patients with previous PCI orcoronary artery bypass grafting (CABG) because of itssuperior ability to localize ischaemia. In patients withangiographically confirmed intermediate coronary lesions,evidence of anatomically appropriate ischaemia is predic-tive of future events, whereas a negative stress imagingtest can be used to define patients with a low cardiac riskwho can be reassured.153

Exercise testing with echocardiography. Exercise stressechocardiography has been developed as an alternative to‘classical’ exercise testing with ECG and as an additionalinvestigation to establish the presence or location andextent of myocardial ischaemia during stress. A restingechocardiogram is acquired before a symptom-limitedexercise test is performed, most frequently using a bicycleergometer, with further images acquired where possible

during each stage of exercise and at peak exercise. Thismay be technically challenging.154 Reported sensitivitiesand specificities for the detection of significant coronarydisease are within a similar range to those described forexercise stress perfusion scintigraphy, sensitivity 53–93%specificity 70–100%, although stress echo tends to be lesssensitive and more specific than stress perfusion scintigra-phy. Depending on the meta-analysis, overall sensitivityand specificity of exercise echocardiography are reportedas 80–85 and 84–86%.155–158 Recent improvements intechnology include improvements in endocardial borderdefinition with the use of contrast agents to facilitateidentification of regional wall motion abnormalities, andthe use of injectable agents to image myocardialperfusion.159–161 Advances in tissue Doppler and strain rateimaging are even more promising.Tissue Doppler imaging allows regional quantification of

myocardial motion (velocity), and strain and strain rateimaging allow determination of regional deformation,strain being the difference in velocity between adjacentregions and strain rate being the difference per unitlength. Tissue Doppler imaging162,163 and strain rateimaging164,165 have improved the diagnostic performanceof stress echocardiography166 improving the capability ofechocardiography to detect ischaemia earlier in the ischae-mic cascade.166,167 Because of the quantitative nature ofthe techniques, inter-operator variability and subjectivityin interpretation of the results are also reduced. Hence,tissue Doppler and strain rate imaging are expected tocomplement current echocardiographic techniques forischaemia detection and improve the accuracy and reprodu-cibility of stress echocardiography in the broader clinicalsetting. There is also some evidence that tissue Dopplerimaging may improve the prognostic utility of stressechocardiography.168

Exercise testing with myocardial perfusion scintigraphy.201Th and 99mTc radiopharmaceuticals are the most com-monly used tracers, employed with single photon emissioncomputed tomography (SPECT) in association with asymptom-limited exercise test on either a bicycle ergometeror a treadmill. Although multiple-view planar images werefirst employed for myocardial perfusion scintigraphy, theyhave been largely replaced by SPECT, which is superiorfrom the standpoint of localization, quantification, andimage quality. Regardless of the radiopharmaceutical used,SPECT perfusion scintigraphy is performed to produce

Table 5 Reasons to terminate the exercise stress test

The exercise stress test is terminated for one of the followingreasons† Symptom limitation, e.g. pain, fatigue, dyspnoea, and

claudication† Combination of symptoms such as pain with significant

ST-changes† Safety reasons such as the following

Marked ST-depression (.2 mm ST-depression can betaken as a relative indication for termination and�4 mm as an absolute indication to stop the test)

ST-elevation �1 mmSignificant arrhythmiaSustained fall in systolic blood pressure .10 mmHgMarked hypertension (.250 mmHg systolic or .115 mmHg

diastolic)† Achievement of maximum predicted heart rate may also be

a reason to terminate the test in patients with excellentexercise tolerance who are not tired and at the discretionof the supervising physician

Table 6 Summary of test characteristics for investigations usedin the diagnosis of stable angina

Diagnosis of CAD

Sensitivity(%)

Specificity(%)

Exercise ECG 68 77Exercise echo 80–85 84–86Exercise myocardial perfusion 85–90 70–75Dobutamine stress echo 40–100 62–100Vasodilator stress echo 56–92 87–100Vasodilator stress myocardial perfusion 83–94 64–90

ESC Guidelines 11

images of regional tracer uptake that reflect relativeregional myocardial blood flow. With this technique, myo-cardial hypoperfusion is characterized by reduced traceruptake during stress in comparison with the uptake atrest. Increased uptake of myocardial perfusion agent inthe lung field identifies patients with severe and extensivecoronary artery disease (CAD)169–172 and stress-induced ven-tricular dysfunction.173 SPECT perfusion provides a moresensitive and specific prediction of the presence of CADthan exercise ECG. Without correction for referral bias,the reported sensitivity of exercise scintigraphy has gener-ally ranged from 70–98%, and specificity from 40–90%,with mean values in the range of 85–90% and 70–75%depending on the meta-analysis.157,158,171,174

Pharmacological stress testing with imaging techniques.Although the use of exercise imaging is preferable wherepossible, as it allows for more physiological reproduction ofischaemia and assessment of symptoms, pharmacologicalstress may also be employed. Pharmacological stress testingwith either perfusion scintigraphy or echocardiography isindicated in patients who are unable to exercise adequatelyor may be used as an alternative to exercise stress. Twoapproaches may be used to achieve this: Either (i) infusionof short-acting sympatho-mimetic drugs such as dobutamine,in an incremental dose protocol which increases myocardialoxygen consumption and mimics the effect of physical exer-cise; or (ii) infusion of coronary vasodilators (e.g. adenosineand dipyridamole) which provide a contrast between regionssupplied by non-diseased coronary arteries where perfusionincreases, and regions supplied by haemodynamically signifi-cant stenotic coronary arteries where perfusion will increaseless or even decrease (steal phenomenon).In general, pharmacological stress is safe and well toler-

ated by patients, with major cardiac complications (includingsustained VT) occuring every 1500 tests with dipyridamole, orone in every 300 with dobutamine.156,175–177 Particular caremust be taken to ensure that patients receiving vasodilators(adenosine or dipyridamole) are not already receiving dipyr-idamole for antiplatelet or other purposes, and that caffeineis avoided in the 12–24 h preceding the study, as it interfereswith their metabolism. Adenosine may precipitate bronchos-pasm in asthmatic individuals, but in such cases dobutaminemay be used as an alternative stressor. Dobutamine does notprovoke as great an increase in coronary blood flow asvasodilator stress, which is a limitation for perfusion scinti-graphy. Thus, for this technique dobutamine is mostlyreserved for patients who cannot exercise and have acontraindication to vasodilator stress.178 The diagnosticperformance of pharmacological stress perfusion andpharmacological stress echo are also similar to that of exer-cise imaging techniques. Reported sensitivity and specificityfor dobutamine stress echo range from 40–100% and62–100%, respectively, and 56–92% and 87–100% for vasodila-tor stress.156,157 Sensitivity and specificity for the detectionof coronary disease with adenosine SPECT range from83–94% and 64–90%.157

On the whole stress echo and stress perfusion scintigra-phy, whether using exercise or pharmacological stress,have very similar applications. The choice as to which isemployed depends largely on local facilities and expertise.Advantages of stress echocardiography over stress perfusionscintigraphy include a higher specificity, the possibility of a

more extensive evaluation of the cardiac anatomy and func-tion, and the greater availability and lower cost, in additionto being free of radiation. However, at least 5–10% ofpatients have an inadequate echo window, and specialtraining in addition to standard echocardiographic trainingis required to correctly perform and interpret stress echo-cardiograms. Nuclear scintigraphy also requires specialtraining for performance and interpretation of the tests.The development of quantitative echocardiographic techni-ques such as tissue Doppler imaging is a step towardsincreasing the inter-observer agreement and reliability ofstress echo.

Non-invasive diagnosis of CAD in patients with LBBB orwith permanent pacemaker in situ remains challenging forboth stress echocardiography and stress scintigraphic tech-niques,179,180 although stress perfusion imaging is markedlyless specific in this setting.181–184 Very poor accuracy isreported for both stress perfusion and stress echocardiogra-phy in patients with ventricular dysfunction associated withLBBB.185 Stress echo has also been shown to have prognosticvalue even in the setting of LBBB.186

Although there is evidence to support superiority of stressimaging techniques over exercise ECG in terms of diagnosticperformance, the costs of using a stress imaging test as firstline investigation in all-comers are considerable. These arenot limited to the immediate financial costs of the individualtest, where some of the cost effectiveness analyses havebeen favourable in certain settings.187,188 But other factorssuch as limited availability of testing facilities and expertise,with consequently increased waiting times for testing themajority of patients attending the evaluation of anginamust also be considered. The resource redistribution andtraining implications of ensuring adequate access for allpatients are considerable, and the benefits to be obtainedby a change from exercise ECG to stress imaging in allpatients are not sufficiently great to warrant recommen-dation of stress imaging as a universal first line investigation.However, stress imaging has an important role to play inevaluating patients with a low pre-test probability ofdisease, particularly women,189–192 when exercise testingis inconclusive, in selecting lesions for revascularization,and in assessing ischaemia after revascularization.193–196

Pharmacologic stress imaging may also be used in the identi-fication of viable myocardium in selected patients with cor-onary disease and ventricular dysfunction in whom a decisionfor revascularization will be based on the presence of viablemyocardium.197,198 A full description of the methods ofdetection of viability is beyond the scope of these guidelinesbut a report on the imaging techniques for the detection ofhibernating myocardium has been previously published byan ESC working group.199 Finally, although stress imagingtechniques may allow for accurate evaluation of changes inthe localization and extent of ischaemia over time and inresponse to treatment, periodic stress imaging in theabsence of any change in clinical status is not recommendedas routine.

Recommendations for the use of exercise stress withimaging techniques (either echocardiography or perfusion)in the initial diagnostic assessment of anginaClass I

(1) Patients with resting ECG abnormalities, LBBB, .1 mmST-depression, paced rhythm, or WPW which prevent

12 ESC Guidelines

accurate interpretation of ECG changes during stress(level of evidence B)

(2) Patients with a non-conclusive exercise ECG butreasonable exercise tolerance, who do not have ahigh probability of significant coronary disease andin whom the diagnosis is still in doubt (level ofevidence B)

Class IIa

(1) Patients with prior revascularization (PCI or CABG) inwhom localization of ischaemia is important (level ofevidence B)

(2) As an alternative to exercise ECG in patients wherefacilities, cost, and personnel resources allow (levelof evidence B)

(3) As an alternative to exercise ECG in patients with a lowpre-test probability of disease such as women withatypical chest pain (level of evidence B)

(4) To assess functional severity of intermediate lesions oncoronary arteriography (level of evidence C)

(5) To localize ischaemia when planning revascularizationoptions in patients who have already had arteriography(level of evidence B)

Recommendations for the use of pharmacological stresswith imaging techniques (either echocardiography orperfusion) in the initial diagnostic assessment of anginaClass I, IIa, and IIb indications as above if the patient is

unable to exercise adequately.

Stress cardiac magnetic resonance. CMR stress testing inconjunction with a dobutamine infusion can be used todetect wall motion abnormalities induced by ischaemia.The technique has been shown to compare favourably todobutamine stress echocardiography (DSE) because ofhigher quality imaging.200 Thus, dobutamine stress CMRhas been shown to be very effective in the diagnosis ofCAD in patients who are unsuitable for dobutamine echocar-diography.201 Studies of outcome following dobutamine CMRshow a low event rate when dobutamine CMR is normal.202

Myocardial perfusion CMR now achieves comprehensiveventricular coverage using multislice imaging. Analysis iseither visual to identify low signal areas of reduced per-fusion, or with computer assistance with quantification ofthe upslope of myocardial signal increase during the firstpass. Although CMR perfusion is still in development forclinical application, the results are already very good incomparison with X-ray coronary angiography, PET, andSPECT.203,204

A recent consensus panel reviewing the currentindications for CMR thus gave class II recommendations forCMR wall motion and CMR perfusion imaging (Class IIprovides clinically relevant information and is frequentlyuseful; other techniques may provide similar information;supported by limited literature).205

Echocardiography at restResting two-dimensional and doppler echocardiography isuseful to detect or rule out the possibility of other disorderssuch as valvular heart disease206 or hypertrophic cardio-myopathy207 as a cause of symptoms, and to evaluate ventri-cular function.155 For purely diagnostic purposes, echo isuseful in patients with clinically detected murmurs,208–211

history and ECG changes compatible with hypertrophic

cardiomyopathy207,212 or previous MI,213,214 and symptomsor signs of heart failure.215–219 Cardiac magnetic resonancemay be also be used to define structural cardiac abnormal-ities and evaluate ventricular function, but routine use forsuch purposes is limited by availability.The true prevalence of isolated diastolic heart failure is

difficult to quantify because of heterogeneity in definitionsand variability in populations studied.220 Community-basedstudies have an independent association between diastolicheart failure and a history of ischaemic heart disease,including angina,221 strengthening the case for echocardio-graphy in all patients with angina, and signs or symptomsof heart failure. Universal resting echocardiography in astable angina population without heart failure may alsoidentify previously undetected diastolic dysfunction.Recent developments in tissue Doppler imaging and strainrate measurement have greatly improved the ability tostudy diastolic function165,222 but the clinical implicationsof isolated diastolic dysfunction in terms of treatment orprognosis are less well defined. Diastolic function mayimprove with anti-ischaemic therapy.223 However, treat-ment of diastolic dysfunction as a primary aim of therapyin stable angina is not yet warranted. There is no indicationfor repeated use of resting echocardiography on a regularbasis in patients with uncomplicated stable angina in theabsence of a change in clinical condition.Although the diagnostic yield of evaluation of cardiac

structure and function in patients with angina is mostlyconcentrated in specific subgroups, estimation of ventri-cular function is extremely important in risk stratification,where echocardiography (or alternative methods ofassessment of ventricular function) has much widerindications.Recommendations for echocardiography for initial

diagnostic assessment of anginaClass I

(1) Patients with abnormal auscultation suggesting valvu-lar heart disease or hypertrophic cardiomyopathy(level of evidence B)

(2) Patients with suspected heart failure (level ofevidence B)

(3) Patients with prior MI (level of evidence B)(4) Patients with LBBB, Q-waves, or other significant

pathological changes on ECG, including ECG LVH(level of evidence C)

Ambulatory ECG monitoringAmbulatory ECG (Holter) monitoring may reveal evidence ofmyocardial ischaemia during normal ‘daily’ activities,224 butrarely adds important diagnostic information in chronicstable angina pectoris over and above that provided by anexercise test.6 Ambulatory silent ischaemia6 has beenreported to predict adverse coronary events and there isconflicting evidence that the suppression of silent ischaemiain stable angina improves cardiac outcome. The significanceof silent ischaemia in this context is different from that inunstable angina where it has been shown that recurrentsilent ischaemia predicts an adverse outcome. Prognosticstudies in stable angina seem to identify silent ischaemiaon ambulatory monitoring as a harbinger of hard clinicalevents (fatal and non-fatal MI) only in highly selectedpatients with ischaemia detectible on exercise testing,

ESC Guidelines 13

and there is little evidence to support its routine deploy-ment as a prognostic implement in this clinical setting.225,226

Ambulatory monitoring may have a role, however, inpatients in whom vasospastic angina is suspected. Finally,in patients with stable angina and suspected major arrhyth-mias, Holter monitoring is an important method of diagnos-ing arrhythmias. Repeated ambulatory ECG monitoring asmeans to evaluate patients with chronic stable angina isnot recommended.Recommendations for ambulatory ECG for initial

diagnostic assessment of anginaClass I

(1) Angina with suspected arrhythmia (level of evidence B)

Class IIa

(1) Suspected vasospastic angina (level of evidence C)

Non-invasive techniques to assess coronary calcificationand coronary anatomyComputed tomography. Although spatial resolution andmovement artefact have for a long time been limitingfactors in computed tomography (CT) cardiac imaging, con-siderable advances in technology have been made in recentyears to overcome these issues. Two modalities of CTimaging have developed to improve spatial and temporalresolution in CT, ultra-fast or electron beam CT (EBCT),and multi-detector or multi-slice CT (MDCT). These havebeen accompanied by improvements in processing softwareto facilitate interpretation of the images acquired. Bothtechniques have been validated as effective in the detectionof coronary calcium and quantification of the extent of cor-onary calcification.227–230 The Agatston score,231 the mostcommonly used score, is based on the area and density ofcalcified plaques. It is computed by specific software andis used to quantify the extent of coronary calcification.Calcium is deposited in atherosclerotic plaques within the

coronary arteries. Coronary calcification increases with age,and nomograms have been developed to facilitate interpret-ation of calcium scores relative to the expected values for agiven age and gender.232 The extent of coronary calcificationcorrelates more closely with the overall burden of plaquethan with the location or severity of stenoses.233 Thus inpopulation-based studies detection of coronary calciummay identify those at higher risk of significant coronarydisease, but assessment of coronary calcification is not rec-ommended routinely for the diagnostic evaluation ofpatients with stable angina.234,235

Image acquisition times and resolution for EBCT and MDCThave been shortened to the extent that CT coronary arterio-graphy can be performed by injection of intravenous contrastagents.236 MDCT or multi-slice CT appears to be the mostpromising of the two techniques in terms of non-invasiveimaging of the coronary arteries, with preliminary studiessuggesting excellent definition, and the possibility of examin-ing arterial wall and plaque characteristics. Sensitivity andspecificity (segment-specific) of CT angiography for thedetection of coronary disease has been reported to be 95and 98%, respectively, using 16-slice CT scanners.237 Studiesusing 64 detector scanning report sensitivities and specifici-ties of 90–94% and 95–97%, respectively, and importantly, anegative predictive value of 93–99%.238,239 Non-invasive CTarteriography holds considerable promise for the future of

the diagnostic assessment of coronary disease. Optimal useof this rapidly developing technology will harness the skillsof both radiology and cardiology disciplines, with cardiologynecessarily taking the lead in selection of patients for inves-tigation by this method, and appropriate management basedon the results. At present, although the diagnostic accuracyof this technique has been reported, the prognostic utility,and the exact place in the hierarchy of investigations instable angina has not yet been fully defined. A conservativesuggestion for its use would be in patients with a lowpre-test (,10%) probability of disease with an equivocalfunctional test (exercise ECG or stress imaging).

Recommendations for the use of CT angiography instable anginaClass IIb

(1) Patients with a low pre-test probability of disease, witha non-conclusive exercise ECG or stress imaging test(level of evidence C)

Magnetic resonance arteriography. Similar to the case of CT,advances in magnetic resonance technology permit non-invasive MR contrast coronary arteriography,205 and holdthe potential for plaque characterization.240 Advantages ofthe technique include the considerable potential for evalu-ation of overall cardiac anatomy and function. However, atpresent this can only be regarded as a valuable tool forresearch and is not recommended as routine clinicalpractice in the diagnostic evaluation of stable angina.

Invasive techniques to assess coronary anatomy

Coronary arteriographyCoronary arteriography is generally undertaken as part of aseries of tests to establish a diagnosis and ascertain treat-ment options. Non-invasive testing can establish the likeli-hood of the presence of obstructive coronary disease withan acceptable degree of certainty, and through appropriaterisk stratification may be used to determine the need forcoronary arteriography for further risk stratification pur-poses. However, it may be contraindicated for reasons ofdisability or serious comorbidity, or offer inconclusiveresults. After a resuscitated cardiac arrest or life threaten-ing ventricular arrhythmia, a definitive diagnosis regardingthe presence or absence of coronary disease is useful inclinical decision-making.241,242 In addition, non-invasivetesting does not allow assessment of suitability for revascu-larization which may be considered for symptomatic as wellas prognostic grounds. Coronary arteriography holds afundamental position in the investigation of patients withstable angina, providing reliable anatomical information toidentify the presence or absence of coronary lumen stenosis,define therapeutic options (suitability of medical treatmentor myocardial revascularization), and determine prognosis.Methods used to perform coronary arteriography haveimproved substantially resulting in the reduction of compli-cation rates and rapid ambulation. The composite rate ofmajor complications associated with routine diagnosticcatheterization in patients is between 1 and 2%. The compo-site rate of death, MI, or stroke is of the order of 0.1–0.2%.243

Intravascular ultrasoundIntravascular ultrasound is a technique that allows pro-duction of ultrasound images from within the (coronary)

14 ESC Guidelines

arteries by passing an ultrasound catheter into the coronaryartery lumen.244 Intravascular ultrasound allows for accu-rate measurement of coronary luminal diameter, assessmentof eccentric lesions and Glagovian remodelling, and quanti-fication of atheroma and calcium deposition. It also allowsfor detailed assessment of interventional target lesions,stent placement, apposition and expansion, and transplantvasculopathy. The technique has afforded advantages interms of our understanding of atherosclerotic plaque depo-sition and progression, offering considerably improvedqualitative and quantitative assessment of coronaryanatomy compared with contrast arteriography and doubt-less, has an important role in specialized clinical settings,particularly as an adjunct to coronary intervention.However, it is more appropriately used in highly specificclinical settings and for research purposes than widespreadapplication as a first line investigation for coronarydisease.245,246

Invasive assessment of functional severity of coronarylesionsThe functional severity of coronary lesions visualized angio-graphically may be assessed invasively by means of measur-ing either the coronary flow velocity (coronary vasodilatoryreserve), or intracoronary artery pressure fractional flowreserve (FFR).7,247 Both techniques involve inducing hyper-aemia through intracoronary injection of vasodilatingagents. The coronary vasodilatory reserve (CVR) is theratio of hyperaemic to basal flow velocity and reflects flowresistance through the epicardial artery and the correspond-ing myocardial bed. It is dependent on microcirculation aswell as severity of the lesion in the epicardial vessel.FFR248 is calculated as the ratio of distal coronary pressureto aortic pressure measured during maximal hyperaemia.A normal value for FFR is 1.0 regardless of the status ofthe microcirculation, and an FFR ,0.75 is deemedpathological.Physiological measurements as described may facilitate

diagnosis in cases of intermediate angiographic stenoses,(visually estimated stenosis 30–70%). FFR measurement hasbeen shown to be useful in differentiating between patientswith favourable long-term outcome (i.e. patients withFFR .0.75) who do not need revascularization; and patientswho require revascularization (i.e. patients withFFR ,0.75)249 but this investigation is best reserved forspecific clinical circumstances or in deciding suitability forrevascularization rather than routine use.Recommendations for coronary arteriography for the

purposes of establishing a diagnosis in stable anginaClass I

(1) Severe stable angina (Class 3 or greater of CanadianCardiovascular Society Classification), with a highpre-test probability of disease, particularly if the symp-toms are inadequately responding to medical treatment(level of evidence B)

(2) Survivors of cardiac arrest (level of evidence B)(3) Patients with serious ventricular arrhythmias (level of

evidence C)(4) Patients previously treated by myocardial revas-

cularization (PCI, CABG) who develop early recurrenceof moderate or severe angina pectoris (level ofevidence C)

Class IIa

(1) Patients with an inconclusive diagnosis on non-invasivetesting, or conflicting results from different non-invasive modalities at intermediate to high risk ofcoronary disease (level of evidence C)

(2) Patients with a high risk of restenosis after PCI if PCIhas been performed in a prognostically important site(level of evidence C)

Risk stratification

The long-term prognosis of stable angina is variable, and therange of treatment options has expanded considerably fromsimple symptomatic control to potent and often expensivestrategies to improve prognosis. When discussing risk strati-fication in stable angina, risk refers primarily to the risk ofcardiovascular death, but the term is often more looselyapplied to incorporate cardiovascular death and MI, or insome cases even wider combinations of cardiovascular end-points. The process of risk stratification serves a dualpurpose, to facilitate an informed response to queriesregarding prognosis from patients themselves, employers,insurers, non-cardiology specialists considering treatmentoptions for comorbid conditions and others, and secondlyto assist in choosing appropriate treatment.For certain management options, particularly revascular-

ization and/or intensified pharmacological therapy, prognos-tic benefit is only apparent in high-risk subgroups, withlimited if any benefit in those whose prognosis is alreadygood. This mandates identification of those patients athighest risk, and therefore most likely to benefit frommore aggressive treatment, early in the assessment ofstable angina.A 10-year cardiovascular mortality of .5% (.0.5% per

annum) is determined to be high risk for the purpose ofimplementing primary prevention guidelines.250 However,absolute levels of what constitutes high-risk and low-riskare not clearly defined for those with establishedCVD.68,251 This problem is linked to difficulties in comparingrisk prediction systems across different populations, deter-mining accuracy of individualized predictions of risk, andsynthesis of multiple components of risk, often studied sep-arately, into an estimate of risk for an individual. Added tocontinuously evolving public and professional perceptionsof what constitutes high- and low-risk over the past fourto five decades (since many of the initial risk predictorswere defined), the reasons for this lack of definition arenot easily overcome.However, while awaiting development of a robust and

portable risk prediction model which incorporates all poten-tial aspects of risk stratification, there is an alternativepragmatic approach, based on clinical trial data. Theinherent problems with bias when interpreting and general-izing clinical trial data must be recognized, but such dataoffer an estimate of the levels of absolute risk achievablewith modern conventional treatment even in patients withproven vascular disease. This in turn facilitates anestimation of what may be accepted as constituting high,low, and intermediate risk in a contemporary setting forthe purposes of determining the threshold for invasiveinvestigation or intensified pharmacological therapy.The cardiovascular mortality and MI rate observed in the

placebo arms of large trials of secondary prevention or

ESC Guidelines 15

anti-anginal therapy in stable coronary disease publishedsince 2000 are illustrated in Figure 1. The rate of cardiovas-cular death in the PEACE252 study was less than 1% perannum, whereas in ‘high-risk’ populations such as in diabeticMICRO-HOPE253 population and the IONA254 population theannualized cardiovascular mortality rate was .2%. For thepurposes of these guidelines, unless qualified differently inthe text, if an individual with angina is determined on thebasis of a well validated risk prediction model, to haveannual cardiovascular mortality of .2% that individual isdeemed high risk, whereas an annual cardiovascular mor-tality of ,1% is considered low risk, and 1–2% intermediaterisk.The clinical evaluation, the response to stress testing,

the quantification of ventricular function, and the extentof CAD are the four key pieces of information to stratifypatient’s risk.66–68,124,255,256 However, not all patients willrequire invasive assessment of the coronary anatomy, par-ticularly if their clinical evaluation and non-invasivetesting establish that they are in a low-risk group. The riskassessment hierarchy can be described as:

(1) Risk stratification by clinical evaluation(2) Risk stratification by response to stress testing(3) Risk stratification by ventricular function(4) Risk stratification by coronary anatomy

The route through these successive tests may not alwaysbe directly linear. For example in a patient with a highpre-test probability of disease, severe angina, and otherhigh-risk clinical features such as signs of heart failure,may proceed directly from clinical evaluation to coronaryarteriography, with perfusion scintigraphy afterwards toevaluate myocardial viability. However, risk stratificationgenerally follows a pyramidal structure, with all patientsrequiring risk stratification by clinical evaluation as themost basic requirement, proceeding in the majority to non-invasive assessment of ischaemia and ventricular function,

and finally coronary arteriography in a selected proportion.A summary of the recommendations for the routine use ofinvestigations in evaluation of stable angina with corre-sponding levels of evidence related to diagnosis and progno-sis, is presented in Table 7, and an algorithm for the initialevaluation of patients presenting with clinical symptomssuggestive of angina is depicted in Figure 2.

Risk stratification using clinical evaluationThe clinical history and physical examination can providevery important prognostic information. ECG can be con-veniently incorporated in risk stratification at this level,and the results of the laboratory tests discussed in the pre-vious section may modify risk estimation further. Diabetes,hypertension, current smoking, and elevated total choles-terol (untreated or elevated despite treatment) have beenshown to be predictive of adverse outcome in patientswith stable angina or other populations with established cor-onary disease.56,58,257–259 Increasing age is an importantfactor to consider, as are prior MI,66,123 symptoms andsigns of heart failure,66,123,124 and the pattern of occurrence(recent onset or progressive), and severity of angina,particularly if unresponsive to therapy.255,260

Pryor et al.261 studied a total of 1030 consecutive out-patients referred to non-invasive testing for suspectedCAD; the information from the initial history, physical exam-ination, ECG, and chest radiograph was used to predict cor-onary anatomy, i.e. the likelihood of any significant coronarydisease, severe disease, and significant left main (LM)disease and to estimate 3 years survival. These estimateswere compared with those based on treadmill testing.Compared with the treadmill exercise test, initialevaluation was slightly better able to distinguish patientswith or without CAD and was similar in the ability toidentify patients at increased risk for dying or with anato-mically severe disease. Although much of the informationobtained by physicians during the initial assessment is

Figure 1 Cardiovascular mortality and myocardial infarction in contemporary trials of stable coronary disease or angina: CAMELOT,467 PEACE,252 ACTION,493

EUROPA,461 HOPE,460 IONA,254 and MICRO-HOPE.253

16 ESC Guidelines

subjective, their study confirms the importance of thatinformation in identifying patients likely to benefit fromfurther testing and supports the development of strategiesthat use the physician’s initial assessment in the evaluationprocess.Typical angina has been shown to be a significant prognos-

tic factor in patients undergoing coronary arteriography,

however, the relation of typical angina to prognosis ismediated by its relation to the extent of coronary disease.But the pattern of angina occurrence, angina frequency,and resting ECG abnormalities are independent predictorsof survival and survival free of MI, and may be combinedin a simple weighted score (Figure 3) to predict outcome,particularly in the first year after assessment.

Table 7 Summary of recommendations for routine non-invasive investigations in evaluation of stable angina

Test For Diagnosis For Prognosis

Class ofrecommendation

Level ofevidence

Class ofrecommendation

Level ofevidence

Laboratory testsFull blood count, creatinine I C I BFasting glucose I B I BFasting lipid profile I B I BHs-C-reactive protein, homocysteine, lp(a), apoA,

and apoBIIb B IIb B

ECGInitial evaluation I C I BDuring episode of angina I BRoutine periodic ECG on successive visits IIb C IIb CAmbulatory ECG monitoringSuspected arrhythmia I BSuspected vasopastic angina IIa CIn suspected angina with normal exercise test IIa C

CXRSuspected heart failure or abnormal

cardiac auscultationI B I B

Suspected significant pulmonary disease I BEchocardiogram

Suspected heart failure, abnormal auscultation,abnormal ECG, Qwaves, BBB, andmarked ST changes

I B I B

Previous MI I BHypertension or diabetes mellitus I C I B/CIntermediate or low-risk patient not due to

have alternative assessment of LV functionIIa C

Exercise ECGFirst line for initial evaluation,

unless unable to exercise/ECG not evaluableI B I B

Patients with known CAD andsignificant deterioration in symptoms

I B

Routine periodic testing once angina controlled IIb C IIb CExercise imaging technique (echo or radionucleotide)

Initial evaluation in patients with uninterpretable ECG I B I BPatients with non-conclusive exercise test

(but adequate exercise tolerance)I B I B

Angina post-revascularization IIa B IIa BTo identify location of ischaemia

in planning revascularizationIIa B

Assessment of functional severity ofintermediate lesions on arteriography

IIa C

Pharmacological stress imaging techniquePatients unable to exercise I B I BPatients with non-conclusive exercise test due to

poor exercise toleranceI B I B

To evaluate myocardial viability IIa BOther indications as for exercise

imaging where local facilities favourpharmacological rather than exercise stress

IIa B IIa B

Non-invasive CT arteriographyPatients with low probability of

disease and non-conclusive or positive stress testIIb C

ESC Guidelines 17

The effect of angina score on prognosis is not apparentafter 3 years and is greatest when ventricular function ismaintained.68,255 This is due to the profound effect ofimpaired ventricular function on prognosis, which whenpresent, greatly outweighs the effect of symptom severity.The association between the pattern of angina occurrence,particularly the development of new onset symptoms,with adverse prognosis may be due to overlap withthe milder end of the spectrum of unstable angina.Furthermore, with more severe angina, the likelihood ofcoronary revascularization for prognostically important

disease increases, which may also contribute to thetime-dependency of symptom severity in predicting risk.

Physical examination may also help in determining risk.The presence of peripheral vascular disease262,263 (eitherlower limb or carotid) identifies patients at increased riskof subsequent cardiovascular events in stable angina. Inaddition, signs related to heart failure (which reflect LVfunction) convey an adverse prognosis.

Patients with stable angina who have resting ECG abnorm-alities: evidence of prior MI, LBBB, left anterior hemiblock,LVH, second or third degree AV block, or AF are at greater

Figure 2 Algorithm for the initial evaluation of patients with clinical symptoms of angina.

18 ESC Guidelines

risk of future cardiovascular events than those with a normalECG.45,264–267 It is possible that in an unselected populationwith stable angina the baseline risk is lower than in many ofthe studies quoted accepting that many of these studieshave been conducted in patients referred for further angio-graphic evaluation.Recommendations for risk stratification by clinical evalu-

ation, including ECG and laboratory tests in stable anginaClass I

(1) Detailed clinical history and physical examinationincluding BMI and/or waist circumference in allpatients, also including a full description of symptoms,quantification of functional impairment, past medicalhistory, and cardiovascular risk profile (level ofevidence B)

(2) Resting ECG in all patients (level of evidence B)

Risk stratification using stress testingStress testing can take the form of exercise or pharmacologi-cal stress with or without imaging. Prognostic informationobtained from stress testing relates not just to detectionof ischaemia as a simple binary response, but also theischaemic threshold, the extent and severity of ischaemia(for imaging techniques), and functional capacity (for exer-cise testing). Stress testing alone is insufficient to assess riskof future events. In addition to the limitations of the differ-ent techniques in the detection of myocardial ischaemia,however small, it must also be recognized that ischaemiaper se is not the only factor which influences the likelihoodof acute events. Several lines of evidence have shown thatthe majority of vulnerable plaques appear angiographicallyinsignificant before their rupture, and may not impinge oncoronary flow to reveal characteristic changes during exer-cise ECG or stress imaging. This may explain the occasionalacute coronary event that occurs shortly after a negativestress test result. Risk stratification with the exercise testshould be a part of a process that includes readily accessibledata from clinical examination and should not take place inisolation. Thus the stress test is performed to provideadditional information regarding the patient’s risk status.Symptomatic patients with suspected or known CAD should

undergo stress testing to assess the risk of future cardiacevents unless cardiac catheterization is urgently indicated.However, no randomized trials of stress testing have beenpublished, and therefore the evidence base consists ofobservational studies only. The choice of initial stress testshould be based on the patient’s resting ECG, physicalability to perform exercise, local expertise, and availabletechnologies.

Exercise ECG. The exercise ECG has been extensively vali-dated as an important tool in risk stratification in sympto-matic patients with known or suspected coronary disease.The prognosis of patients with a normal ECG and a low clini-cal risk for severe CAD is excellent. In one study in which 37%of outpatients referred for non-invasive testing met thecriteria for low risk261 fewer than 1% had LM stem arterydisease or died within 3 years. Lower-cost options such astreadmill testing should therefore be used, whenever pos-sible, for initial risk stratification, and only those withabnormal results should be referred to arteriography.The prognostic exercise testing markers include exercise

capacity, blood pressure response, and exercise-inducedischaemia (clinical and ECG). Maximum exercise capacityis a consistent prognostic marker, this measure is at leastpartly influenced by the extent of rest ventricular dysfunc-tion and the amount of further LV dysfunction induced byexercise.139,268 However, exercise capacity is also affectedby age, general physical condition, comorbidites, andpsychological state. Exercise capacity may be measured bymaximum exercise duration, maximum MET level achieved,maximum workload achieved in Watts, maximum heart rate,and double (rate–pressure) product. The specific variableused to measure exercise capacity is less important thanthe inclusion of this marker in the assessment. In patientswith known CAD and normal, or mildly impaired LV function,5-year survival is higher in patients with a better exercisetolerance.123,139,152,269,270

Other prognostic exercise testing markers are related toexercise-induced ischaemia and markers include changesin ST-segment (depression or elevation), and exercise-induced angina. McNeer et al.270 demonstrated that anearly positive exercise test (ST-depression .1 mm in thefirst two stages of the Bruce protocol) identified a high-riskpopulation, whereas patients who could exercise into stageIV were at low risk regardless of the ST response. ST-segmentelevation is observed most frequently in patients with ahistory of MI; in patients without infarction, ST-elevationduring exercise has been associated with severe transmuralmyocardial ischaemia.In the CASS Registry, 12% of medically treated patients

were identified as high risk on the basis of �0.1 mV ofexercise-induced ST-segment depression and inability tocomplete stage I of the Bruce protocol. These patients hadan average mortality rate of 5% per year. Patients whocould exercise to at least stage III of the Bruce protocolwithout ST changes (34%) constituted the low-risk group(estimated annual mortality, less than 1%).123

Several studies have attempted to incorporate multipleexercise variables into a prognostic score. The clinicalvalue of stress testing is improved considerably by

Figure 3 Prognostic angina score. The pattern of angina occurrence can be used to predict prognosis.80

ESC Guidelines 19

multivariable analysis including several exercise variables ina given patient such as the combination of heart rate atpeak exercise, ST-segment depression, the presence orabsence of angina during the test, peak workload, andST-segment slope.152,271–273

The Duke treadmill score (DTS) is a well validated scorewhich combines exercise time, ST-deviation, and anginaduring exercise to calculate the patient’s risk.152,272 TheDTS equals the exercise time in minutes minus (five timesthe ST-segment deviation, during or after exercise in milli-metres) minus (four times the angina index, which has avalue of ‘0’ if there is no angina, ‘1’ if angina occurs, and‘2’ if the angina is the reason for stopping the test(Figure 4). In the original description of this score in a popu-lation with suspected CAD, two-thirds of patients withscores indicating low-risk had a 4-year survival rate of 99%(average annual mortality rate 0.25%), and the 4% who hadscores indicating high-risk had a 4-year survival rate of 79%(average annual mortality rate 5%). The combination ofexercise and clinical parameters, with or without the useof scores such as the DTS, has been shown to be an effectivemethod of discriminating between high- and low-risk groupswithin a population presenting with known or suspectedcoronary disease (Figure 5).

Stress echocardiography. Stress echocardiography may alsobe used effectively to stratify patients according to theirrisk of subsequent cardiovascular events158,274 and similarlyhas an excellent negative predictive value,275,276 in patientswith a negative test having a hard event rate (death or MI) of,0.5%/year. The risk of future events is influenced both bythe number of resting regional wall motion abnormalitiesand inducible wall motion abnormalities on stress echocar-diography, with more resting abnormalities and a greateramount of inducible ischaemia associated with higherrisk.155 Identification of a high risk cohort allows for appro-priate further investigation and/or intervention.

Stress perfusion scintigraphy. SPECT perfusion scintigraphyis a useful method of non-invasive risk stratification,readily identifying those patients at greatest risk for sub-sequent death and MI. Normal stress myocardial perfusionimages are highly predictive of a benign prognosis. Severalstudies involving thousands of patients have found that anormal stress perfusion study is associated with a sub-sequent rate of cardiac death and MI of less than 1% peryear, which is nearly as low as that of the general popu-lation.169,170,277 The only exceptions would appear inpatients with normal perfusion images with either a high-risk treadmill ECG score or severe resting LV dysfunction.278

In contrast, abnormal findings on stress perfusionscintigraphy have been associated with severe CAD, and

subsequent cardiac events. Large stress-induced perfusiondefects, defects in multiple coronary artery territories,transient post-stress ischaemic LV dilatation, and in patientsstudied with 201Th, increased lung uptake279 on post-exercise or pharmacological stress images are all adverseprognostic indicators.158,174,277,278

The results of planar and SPECT perfusion scintigraphy canbe used to identify a ‘high-risk’ patient subset. Thesepatients, who have a greater than 3% annual mortalityrate, should be considered for early coronary arteriography,as their prognosis may be improved by revascularization.Exercise scintigraphy offers greater prognostic informationthan pharmacological stress imaging because of the infor-mation regarding symptoms, exercise tolerance, andhaemodynamic response to exercise which is additive tothat obtained from perfusion data alone.

Recommendations for risk stratification according toexercise stress ECG in stable angina in patients who canexerciseClass I

(1) All patients without significant resting ECG abnormal-ities undergoing initial evaluation (level of evidence B)

(2) Patients with stable coronary disease after a significantchange in symptom level (level of evidence C)

Class IIa

(1) Patients post-revascularization with a significantdeterioration in symptomatic status (level of evidenceB)

Recommendations for risk stratification according toexercise stress imaging (perfusion or echocardiography)in stable angina in patients who can exerciseClass I

(1) Patients with resting ECG abnormalities, LBBB, .1 mmST-depression, paced rhythm, or WPW which preventaccurate interpretation of ECG changes during stress(level of evidence C)

(2) Patients with a non-conclusive exercise ECG, but inter-mediate or high probability of disease (level of evidenceB)

Class IIa

(1) In patients with a deterioration in symptoms post-revascularization (level of evidence B)

(2) As an alternative to exercise ECG in patients wherefacilities, cost, and personnel resources allow (levelof evidence B)

Recommendations for risk stratification according topharmacological stress imaging (perfusion or echocardio-graphy) in stable anginaClass I

(1) Patients who cannot exercise

Other class I and II indications as for exercise stressimaging (perfusion or echocardiography) in stable angina inpatients who can exercise, but where local facilities donot include exercise imaging.

Risk stratification using ventricular functionThe strongest predictor of long-term survival is LV function.In patients with stable angina as LV ejection fraction (EF)Figure 4 Duke treadmill score.272

20 ESC Guidelines

declines, mortality increases. A resting EF of less than 35% isassociated with an annual mortality rate greater than 3% peryear.67,123,124,280

Long-term follow-up data from the CASS registry showedthat 72% of the deaths occurred in the 38% of the populationthat had either LV dysfunction or severe coronary disease.The 12-year survival rate of patients with EF .50% was35–49%280 and ,35% were 73, 54, and 21%, respectively(P, 0.0001). The prognosis of patients with a normal ECGand low clinical risk for severe CAD is, on the other hand,excellent.261

Ventricular function affords additional prognostic infor-mation to coronary anatomy, with reported 5-year survivalrates of a man with stable angina and three-vessel diseaseranging from 93% in those with normal ventricular functionto 58% with reduced ventricular function.67 Impaired ventri-cular function may be inferred from extensive Q-wave onECG, symptoms or signs of heart failure, or measured non-invasively by echocardiography, radionuclide techniques orcontrast ventriculography at the time of coronaryarteriography.Clinical evaluation as outlined earlier may indicate which

patients have heart failure, and thus at substantiallyincreased risk for future cardiovascular events. However,the prevalence of asymptomatic ventricular dysfunction isnot inconsiderable,281–283 and has been reported to be ashigh as twice that of clinical heart failure, with the presenceof ischaemic heart disease a major risk factor for itsoccurrence.Ventricular dimensions have been shown to contribute

useful prognostic information which is incremental to theresults of exercise testing in a stable angina population with2-year follow-up.284 In a study of hypertensive patientswithout angina, the use of echocardiography to assess ventri-cular structure and function was associated with reclassifica-tion from medium/low risk to high risk in 37% of patients,285

and the European guidelines for the management of hyper-tension recommend an echocardiogram for patients with

hypertension.286 Diabetic patients with angina also requireparticular attention. Echocardiography in diabetic individualswith angina has the advantage of identifying LVH and diastolicas well as systolic dysfunction, all of which are more prevalentin the diabetic population. Thus, an estimation of ventricularfunction is desirable in risk stratification of patients withstable angina, and an assessment for ventricular hypertrophy(by echocardiography or MRI), as well as assessment of ventri-cular function is particularly pertinent in patients with hyper-tension or diabetes. For most other patients the choice ofinvestigation to determine ventricular function will be depen-dent on the other tests which have been performed or areplanned, or the level of risk estimated by other methods. Forexample, in a patient who has a stress imaging test it may bepossible to estimate ventricular function from this testwithout additional investigation, or a patient scheduled tohave coronary arteriography on the basis of a strongly positiveexercise test at low workload, in the absence of prior MI, orother indications for echocardiography, may have ventricularsystolic function assessed at the time of arteriography.Recommendations for risk stratification by echocardio-

graphic evaluation of ventricular function in stable anginaClass I

(1) Resting echocardiography in patients with prior MI,symptoms or signs of heart failure, or resting ECGabnormalities (level of evidence B)

(2) Resting echocardiography in patients with hypertension(level of evidence B)

(3) Resting echocardiography in patients with diabetes(level of evidence C)

Class IIa

(1) Resting echocardiography in patients with a normalresting ECG without prior MI who are not otherwise tobe considered for coronary arteriography (level ofevidence C)

Figure 5 Prognostic stratification according to combined clinical and exercise variables.52,270–273,681–683

ESC Guidelines 21

Risk stratification using coronary arteriographyDespite the recognized limitations of coronary arteriographyto identify vulnerable plaques which are likely to lead toacute coronary events, the extent, severity of luminalobstruction, and location of coronary disease on coronaryarteriography have been convincingly demonstrated to beimportant prognostic indicators in patients withangina.67,124,287,288

Several prognostic indices have been used to relatedisease severity to the risk of subsequent cardiac events;the simplest and most widely used is the classification ofdisease into one vessel, two vessel, three vessel, or LMCAD. In the CASS registry of medically treated patients,the 12-year survival rate of patients with normal coronaryarteries was 91% compared with 74% for those with one-vessel disease, 59% for those with two vessel disease and50% for those with three vessel disease (P , 0.001).280

Patients with severe stenosis of the LM coronary arteryhave a poor prognosis when treated medically. The presenceof severe proximal left anterior descending artery (LAD)disease also significantly reduces the survival rate. The5-year survival rate with three-vessel disease plus greaterthan 95% proximal LAD stenosis was reported to be 54% com-pared with a rate of 79% with three-vessel disease withoutLAD stenosis.288 However, it should be appreciated that inthese ‘older’ studies preventive therapy was not at thelevel of current recommendations regarding both lifestyleand drug therapy. Accordingly, absolute estimates of riskderived from these studies, in general, over-estimate therisk of future events.Recent angiographic studies indicate that a direct corre-

lation exists between the angiographic severity of coronarydisease and the amount of angiographically insignificantplaques in the coronary tree.289 The higher mortality ratesin patients with multivessel disease may be a consequenceof a higher number of mildly stenotic and non-stenoticplaques that are potential sites for acute coronary eventsthan those with one-vessel disease.The major focus in non-invasive risk stratification is on

subsequent patient mortality, with the rationale to identifypatients in whom coronary arteriography and subsequentrevascularization might decrease mortality, that is thosewith three-vessel disease, LM CAD, and proximal anteriordescending CAD.69,290

When appropriately used, non-invasive tests have anacceptable predictive value for adverse events; this ismost true when the pre-test probability of severe CAD islow. When the estimated annual cardiovascular mortalityrate is less than or equal to 1%, the use of coronary arterio-graphy to identify patients whose prognosis can be improvedis likely to be inappropriate; in contrast it is appropriate forpatients whose cardiovascular mortality risk is greater than2% per annum. Decisions regarding the need to proceed toarteriography in the intermediate risk group, those with anannual cardiovascular mortality of 1–2% should be guidedby a variety of factors including the patient’s symptoms,functional status, lifestyle, occupation, comorbidity, andresponse to initial therapy.With increasing public and media interest in available

medical technology, widespread access to the internet andother sources of information, patients will often have con-siderable information regarding investigation and treatmentoptions for their condition. It is the duty of the physician to

ensure that the patient is fully informed of their risk andthe potential benefits or lack of benefit of any particularprocedure, and to guide their decision appropriately.Some patients may still consider medical treatmentrather than intervention, or an element of doubt regardingdiagnosis, to be unacceptable regardless of the evidencepresented to them. Coronary arteriography should not beperformed in patients with angina who refuse invasive pro-cedures, prefer to avoid revascularization, who are notcandidates for PCI or CABG, or in whom it will not improvequality of life.

Recommendations for risk stratification by coronaryarteriography in patients with stable anginaClass I

(1) Patients determined to be at high risk for adverseoutcome on the basis of non-invasive testing even ifthey present with mild or moderate symptoms ofangina (level of evidence B)

(2) Severe stable angina (Class 3 of CanadianCardiovascular Society Classification (CCS), particularlyif the symptoms are inadequately responding tomedical treatment (level of evidence B)

(3) Stable angina in patients who are being considered formajor non-cardiac surgery, especially vascular surgery(repair of aortic aneurysm, femoral bypass, carotidendarterectomy) with intermediate or high risk fea-tures on non-invasive testing (level of evidence B)

Class IIa

(1) Patients with an inconclusive diagnosis on non-invasivetesting, or conflicting results from different non-invasive modalities (level of evidence C)

(2) Patients with a high risk of restenosis after PCI if PCIhas been performed in a prognostically important site(level of evidence C)

Special diagnostic considerations: anginawith ‘normal’ coronary arteries

The clinicopathological correlation of symptoms with coron-ary anatomy varies widely in angina from typical symptomsof angina due to significant coronary lesions causing transi-ent ischaemia when myocardial demand is increased, toclearly non-cardiac chest pain with normal coronary arteries

Figure 6 Schematic representation of clinico-pathological variants inangina.

22 ESC Guidelines

on the other end of the spectrum. Spanning the extremes ofthis spectrum are a number of clinicopathological correlateswhich may overlap to a greater or lesser extent with eachother (Figure 6). These range from atypical anginal symp-toms with significant coronary stenoses, which would fallunder the umbrella of the conventional diagnosis of anginapectoris, to typical anginal symptoms with angiographicallynormal coronary arteries which might be described ascardiac Syndrome X. Vasospastic angina, caused by dynamiccoronary obstruction in coronary arteries which may beeither angiographically smooth or significantly stenosed, is afurther factor to be considered in the diagnosis. A consider-able proportion of patients, especially women, who undergocoronary arteriography because of symptoms of chest paindo not have significant CAD.291 In these patients, the featuresof chest pain may suggest one of the following threepossibilities.

. Pain involves a small portion of the left hemithorax, lastsfor several hours or even days, is not relieved by nitrogly-cerin, and may be provoked by palpation (non-anginalpain, often musculoskeletal in origin)

. Pain has typical features of angina in terms of location andduration but occurs predominantly at rest (atypicalangina, which may be due to coronary spasm vasospasticangina)

. Angina with mostly typical features (although durationmay be prolonged, and relation to exercise somewhatinconsistent) associated with abnormal results of stresstests (cardiac Syndrome X)

Detailed discussion of the management of the first groupis beyond the scope of these guidelines. With regard tothe ‘atypical angina’ group, in general this term refers tosymptoms with any two of the three main features oftypical angina pectoris as outlined in Table 2, and theterm may be used interchangeably with ‘probable angina’.Suspected vasospastic angina is a specific subgroup of atypi-cal angina which is atypical only in that it lacks a consistentassociation with exercise. Other forms of atypical angina arenot discussed separately, but a brief description of the diag-nostic evaluation of cardiac Syndrome X and vasospasticangina are outlined below.

Syndrome XClinical picture. Although there is no universally accepteddefinition of Syndrome X, to fulfil the classical descriptionof ‘Syndrome X’292 requires the presence of the triad of:

(1) Typical exercise-induced angina (with or withoutadditional resting angina and dyspnoea)

(2) Positive exercise stress ECG or other stress imagingmodality

(3) Normal coronary arteries

Chest pain occurs frequently and anginal attacks areusually encountered several times per week, but with astable pattern. Therefore, Syndrome X resembles chronicstable angina. However, the clinical presentation of patientsincluded in ‘Syndrome X’ studies is highly variable and anginaat rest is often encountered in addition to exercise-provokedchest pain.293 Severe attacks of resting angina may promptrecurrent emergency presentations, and hospital admissionswith an inaccurate diagnosis of unstable angina leading toinappropriate diagnostic and therapeutic procedures.

In a subset of patients with Syndrome X, microvasculardysfunction can be demonstrated and this entity is com-monly referred to as ‘microvascular angina’.294

Arterial hypertension, either with or without associatedventricular hypertrophy, is frequently encountered in thepopulation with chest pain and ‘normal coronary arteries’.Hypertensive heart disease is characterized by endothelialdysfunction,295 LVH, interstitial and perivascular fibrosis withdiastolic dysfunction296 changes in myocardial and coronaryultrastructure.297 and reduced coronary flow reserve.298

Together or separately these changes may compromisecoronary blood flow relative to myocardial oxygen demand,causing angina. For the most part, treatment in such casesshould focus on control of hypertension to restore functionaland structural integrity of the cardiovascular system.299

Pathogenesis. The mechanism of chest pain in patients withangina despite a normal coronary angiogram continues to becontroversial. Functional abnormalities of the coronarymicrocirculation during stress, including abnormal dilatorresponses and a heightened response to vasoconstrictors,have been considered potential mechanisms of chest painand ischaemic-appearing ST-segment depression duringexercise.300 However, others failed to find haemodynamicor metabolic evidence of ischaemia in many patients withSyndrome X301 but propose abnormal cardiac sensitivity(coupled with some impairment in coronary flow reserve)in these patients that may lead to chest pain on a non-ischaemic basis.302

Prognosis. Although the prognosis in terms of mortality ofpatients with Syndrome X appears to be favourable,303 themorbidity of patients with Syndrome X is high304,305 andthe condition is frequently associated with continuing epi-sodes of chest pain and hospital readmission.306 There isemerging evidence that identification of impaired endo-thelial dysfunction in this patient population may identifya subgroup at risk for the future development of athero-sclerotic coronary disease307 and with a less benign progno-sis than previously thought.305,308–310

Diagnosis of Syndrome X. Diagnosis and management ofpatients with chest pain and normal coronary arteries rep-resent a complex challenge. The diagnosis of Syndrome Xmay be made if a patient with exercise-induced angina hasnormal or non-obstructed coronary arteries by arteriographybut objective signs of exercise-induced ischaemia(ST-depression in exercise ECG, ischaemic changes by scinti-graphy). It is necessary to differentiate this pain from non-cardiac chest pain caused by oesophageal dysmotility, fibro-myalgia, or costochondritis. Coronary artery spasm shouldbe excluded by appropriate provocation tests. Endothelialdysfunction may be identified by epicardial coronaryartery diameter response to acetylcholine. Invasive testingusing acetylcholine provocation can serve a dual purposeby excluding vasospasm and unmasking endothelial dysfunc-tion, which may be associated with a worse prognosis. Incertain circumstances, for example in the presence of anextensive radionuclide perfusion defect or wall motionabnormality during stress testing and an angiographicallyirregular artery, intracoronary ultrasound may be consideredto exclude missed obstructive lesions. The excellent progno-sis when endothelial dysfunction is not present needs to be

ESC Guidelines 23

emphasized and the patient should be informed and reas-sured about the benign course of the condition.Recommendations for investigation in patients with

classical triad of Syndrome XClass I

(1) Resting echocardiogram in patients with angina andnormal or non-obstructed coronary arteries to assessfor presence of ventricular hypertrophy and/or dias-tolic dysfunction (level of evidence C)

Class IIb

(1) Intracoronary acetylcholine during coronary arterio-graphy, if the arteriogram is visually normal, to assessendothelium-dependent coronary flow reserve, andexclude vasospasm (level of evidence C)

(2) Intracoronary ultrasound, coronary flow reserve, or FFRmeasurement to exclude missed obstructive lesions, ifangiographic appearances are suggestive of a non-obstructive lesion rather than completely normal, andstress imaging techniques identify an extensive areaof ischaemia (level of evidence C)

Vasospastic/variant anginaClinical picture. Patients with variant or vasospastic anginapresent with typically located pain, which occurs at rest,but does not, or only occasionally, occurs with exertion.Such pain characteristics are often caused by coronaryartery spasm, especially when the pain occurs at night andin the early morning hours.311 If the chest pain is severe,this may lead to hospital admission. Nitrates usually relievethe pain within minutes. The terms vasospastic or variantangina may be used to describe such symptoms, although‘Prinzmetal angina’312 has also been used. This term wasinitially used to describe patients with clearly documentedST-elevation during chest pain due to coronary spasm.Angina at rest with preserved exercise tolerance may alsobe associated with significant obstructive coronary diseasewithout demonstrable vasospasm, and management is as out-lined for typical symptoms. In the case of chest pain withoutsignificant coronary disease or coronary spasm, and no demon-strable ischaemia, non-cardiac causes of pain should be con-sidered and conventional primary prevention adhered to.Asubstantialproportionofpatientswithahistorysuggestive

ofvasospasticanginahaveobstructivecoronarydisease313andin such patients vasospastic angina may co-exist with typicalexertional angina due to fixed coronary lesions. Non-exertional symptoms due to vasospasm may also occur inpatients with minimal or no angiographically evident coron-ary disease, and typical exertional angina and dyspnoeamay also occur in patients with vasospasm but entirelynormal coronary arteries. This indicates some overlap withpatients suffering from Syndrome X (Figure 6).314 The preva-lence of vasospastic angina is difficult to assess, not leastbecause of its overlap with typical angina and Syndrome X.Vasospasm may occur in response to smoking, electrolytedisturbances (potassium, magnesium), cocaine use, coldstimulation, autoimmune diseases, hyperventilation orinsulin resistance. There is also an ethnic pre-disposition,with a higher prevalence in Japanese populations.

Pathogenesis. The mechanisms leading to vasospastic anginaare not entirely clear, but hyperreactivity of smooth musclecells of the involved coronary segment315 may play a role,

and endothelial dysfunction may also be involved.316,317 Thecauses of smooth muscle cell hyperreactivity are unknown,but several possible contributing factors have beensuggested, including increased cellular rho-kinase activity,318

abnormalities in ATP-sensitive potassium channels,319 andmembrane Naþ-Hþ countertransport.320 Other contributingfactors may be imbalances in the autonomic nervoussystem,321,322 enhanced intracoronary concentrations ofvasoconstricting substances, such as endothelin,323 andhormonal changes, such as post-oopherectomy.324,325

Natural history and prognosis. The prognosis of vasospasticangina depends on the extent of underlying CAD. Deathand MI are not frequent in patients without angiographicallysignificant obstructive disease, but do occur.326 Coronarydeath in the population with non-obstructive lesions hasbeen reported as �0.5% per annum,327,328 but those withspasm superimposed on stenotic lesions do significantlyless well.327,329–332

Diagnosis of vasospastic anginaElectrocardiography. The ECG during vasospasm is classicallydescribed as showing ST-elevation.312 In others, ST-depressioncan be documented,333 whereas others may show noST-segment shift at all.334,335 However, as attacks tend toresolve quickly, 12-lead ECG documentation tends to be diffi-cult. Repeated 24 h ECG monitoring may be able to captureST-segment shifts associated with anginal symptoms inthese patients.336

Coronary arteriography. Although the demonstration ofST-elevation at the time of angina and a normal coronaryarteriogram make the diagnosis of variant angina highlylikely, there is often uncertainty about the diagnosis inless well-documented or clinically less straight forwardcases. Moreover, there is no unanimously accepted definitionof what constitutes coronary vasospasm.

Spontaneous spasm during coronary arteriography is onlyoccasionally observed in patients with symptoms suggestiveof vasospastic angina. Hence, provocation tests are com-monly used to demonstrate the presence of coronary vasos-pasm.337 Hyperventilation and the cold pressor test haveonly a rather limited sensitivity for the detection ofcoronary spasm.338 Thus, acetylcholine injections into thecoronary artery339 are used in most centres today, but intra-coronary ergonovine provocation gives similar results.340,341

Acetylcholine is injected in incremental doses of 10, 25, 50and 100 mg separated by 5 min intervals. Intravenous ergo-novine may also be used but may be associated with morediffuse spasm, which is not desirable.

Coronary spasm may be focal or diffuse.335 Lumenreductions between 75 and 99% when compared with thediameter following nitroglycerin injection are defined asspasm in the literature,342,343 whereas lumen reductions,30% are commonly seen in non-spastic coronary seg-ments344 and may represent the ‘physiological’ constrictorresponse to acetylcholine provocation.342

Acetylcholine or ergonovine provocation of coronaryspasm is a safe test,341,345 if the agent is infused selectivelyinto each of the three major coronary arteries. Non-invasiveintravenous ergonovine provocative testing has also beendescribed with the addition of echocardiographic or per-fusion scintigraphy to electrocardiographic monitoringincreasing the sensitivity and specificity of these

24 ESC Guidelines

tests.346,347 However, invasive documentation of vasospasmremains the gold standard against which diagnostic testsare evaluated, and as fatal complications due to prolongedspasm involving multiple vessels may occur with intravenousinjection of ergonovine,348 the intracoronary route is pre-ferred. Provocative testing without coronary arteriographyor provocative testing in patients with high-gradeobstructive lesions on coronary arteriography are notrecommended.Recommendations for diagnostic tests in suspected

vasospastic anginaClass I

(1) ECG during angina if possible (level of evidence B)(2) Coronary arteriography in patients with characteristic

episodic chest pain and ST-segment changes thatresolve with nitrates and/or calcium antagonists todetermine the extent of underlying coronary disease(level of evidence B)

Class IIa

(1) Intracoronary provocative testing to identify coronaryspasm in patients with normal findings or non-obstructive lesions on coronary arteriography and theclinical picture of coronary spasm (level of evidence B)

(2) Ambulatory ST-segment monitoring to identifyST-deviation (level of evidence C)

Treatment

Aims of treatment

To improve prognosis by preventing MI and death. Efforts toprevent MI and death in coronary disease focus primarily onreducing the incidence of acute thrombotic events and thedevelopment of ventricular dysfunction. These aims areachieved by lifestyle or pharmacological interventionswhich (i) reduce plaque progession, (ii) stabilize plaque,by reducing inflammation and preserving endothelial func-tion, and finally (iii) by preventing thrombosis if endothelialdysfunction or plaque rupture occur. In certain circum-stances, such as in patients with severe lesions in coronaryarteries supplying a large area of jeopardized myocardium,revascularization offers additional opportunities toimprove prognosis by improving existing perfusion or provid-ing alternative routes of perfusion.

To minimize or abolish symptoms. Lifestyle changes, drugs,and revascularization all have a role to play in minimizing oreradicating symptoms of angina, although not necessarily allin the same patient.

General management

Patients and their close associates should be informed of thenature of angina pectoris, and the implications of the diag-nosis and the treatments that may be recommended. Thepatient can be reassured that, in most cases, both the symp-toms of angina and prognosis can be improved with propermanagement. Comprehensive risk stratification should beconducted as outlined above, and particular attentionshould be paid to the elements of lifestyle that could havecontributed to the condition and which may influence prog-nosis, including physical activity, smoking, and dietaryhabits. The recommendations of the Third Joint European

Societies’ Task Force250 on Cardiovascular DiseasePrevention in Clinical Practice should be followed.

Treatment of the acute attackPatients should be advised to rest, at least briefly, from theactivity which provoked the angina and advised regardingthe use of sublingual nitrate for acute relief of symptoms.It is also useful to warn the patient of the need to protectagainst potential hypotension by sitting on the firstnumber of occasions when taking sublingual nitrate andalso other possible side-effects, particularly headache. Theuse of prophylactic nitrate to prevent predictable episodesof angina in response to exertion can be encouraged.Patients should be informed of the need to seek medicaladvice if angina persists for .10–20 min after resting and/or is not relieved by sublingual nitrate.All preventive measures, pharmacological and non-

pharmacological, described in this document apply similarlyto men and women,349 even if there is less documentation ofhealth benefits among female compared with male patientswith stable angina pectoris and the clinical presentation ofthe disease may differ between genders. Risk factors, clini-cal presentation, and the level of risk for serious cardiovas-cular complications should determine the need forpreventive and therapeutic interventions, rather than thegender of the patient. Recommendations concerninghormone replacement therapy have changed and are com-mented upon subsequently.

SmokingCigarette smoking should be strongly discouraged, as thereis abundant evidence that it is the most important reversiblerisk factor in the genesis of coronary disease in manypatients.350,351 Cessation of smoking greatly improves bothsymptoms and prognosis. Patients often require specialhelp in abandoning their addiction, and nicotine replace-ment therapy has proved effective and safe in helpingpatients with CAD to quit smoking.352–355

Diet and alcoholDietary interventions are effective in the prevention ofevents in patients with established CAD, when properlyimplemented.1 Certain food types are to be encouragedsuch as fruit, vegetables, cereal, and grain products as wellas skimmed dairy products, fish, and lean meat, many ofwhich are major components of the Mediterranean diet.Patients should thus be encouraged to adopt a ‘Mediterra-nean’ diet, with vegetables, fruit, fish, and poultry beingthe mainstays. The intensity of change needed in the dietmay be guided by the total and LDL cholesterol levels andother lipid abnormalities.356 Those who are overweightshould be put on a weight reducing diet.Alcohol in moderation may be beneficial,357 but excessive

consumption is harmful, especially in patients with hyper-tension or heart failure. It has been difficult to developpublic health recommendations on safe limits of alcoholuse, but moderate alcohol consumption should not bediscouraged.1,358–360

Omega-3 fatty acidsFish oils rich in omega-3 fatty acids (n-3 polyunsaturatedfatty acids) are useful in the reduction of hypertriglyceri-daemia, and in the GISSI-Prevenzione trial, supplementation

ESC Guidelines 25

with one fish oil capsule (Omacor) daily was shown to reducethe risk of sudden death in patients (85% men) with a recentMI.361 A detailed further analysis of the GISSI-Prevenzionetrial362 showed an early reduction of cardiovascular deathwhich was dependent on fewer sudden deaths. The effectwas attributed to antiarrhythmic effects of omega-3 fattyacid supplementation, in agreement with previous experimen-tal data.362 A meta-analysis of omega-3 fatty acid supplemen-tation363 confirmed the effect on sudden death and showed areduction of mortality, but concluded that reasonably largerisk reduction with such therapy can only be expectedamong high-risk patients, such as patients with a recent MI.A more recent meta-analysis of the effects of lipid-loweringtherapies on mortality also confirmed the beneficial effectof n-3 fatty acids in secondary prevention.364 Patients withstable angina without high risk features should rarely beconsidered for omega-3 fatty acid supplementation. Dietaryintervention to achieve fish consumption at least onceweekly can, however, be more widely recommended.365,366

Vitamins and antioxidantsVitamin supplementation has not been shown to reducecardiovascular risk in patients with CAD. In contrast to theabove-mentioned findings with dietary intervention,several large studies have failed to find benefits frompharmacological supplementation with antioxidantvitamins.367–369

Hypertension, diabetes, and other disordersConcomitant disorders should be managed appropriately.Particular attention should be given to control of elevatedblood pressure, diabetes mellitus, and other features ofthe metabolic syndrome which increase the risk of pro-gression of coronary disease. Of particular note, the TaskForce report on CVD prevention250 suggests considering alower threshold for institution of pharmacological therapyfor hypertension (130/85) for patients with establishedCHD (which would include patients with angina and non-invasive or invasive confirmation of coronary disease).Patients with concomitant diabetes and/or renal diseaseshould be treated with a blood pressure goal of ,130/80 mm Hg.286 Diabetes is a strong risk factor for cardiovascu-lar complications and should be managed carefully withgood glycaemic control and attention to other riskfactors.286,370,371

Multifactorial intervention in diabetic patients mayindeed reduce both cardiovascular and other diabetic com-plications markedly.372 Recently, the addition of pioglitizoneto other hypoglycaemic medication has been shown toreduce the incidence of death, non-fatal MI, or stroke (asecondary endpoint) in patients with type 2 diabetes andvascular disease by 16%; the primary composite endpoint,which included a number of vascular endpoints, was notsignificantly reduced.373 Anaemia or hyperthyroidism, ifpresent, should be corrected.

Physical activityPhysical activity within the patient’s limitations should beencouraged, as it may increase exercise tolerance, reducesymptoms, and has favourable effects on weight, bloodlipids, blood pressure, glucose tolerance, and insulin sensi-tivity. Advice on exercise must take into account the

individual’s overall fitness and the severity of symptoms.An exercise test can act as a guide to the level at whichan exercise programme can be initiated. Detailed rec-ommendations on exercise prescription and on recreationaland vocational activities are provided by the ESC WorkingGroup on Cardiac Rehabilitation.150

Psychological factorsAlthough the role of stress in the genesis of CAD is controver-sial, there is no doubt that psychological factors are import-ant in provoking attacks of angina. Furthermore, thediagnosis of angina often leads to excessive anxiety.Reasonable reassurance is essential, and patients maybenefit from relaxation techniques and other methods ofstress control. Appropriate programmes may reduce theneed for drugs and surgery.374 A randomized controlledtrial375 of a self-management plan showed an apparentimprovement in the psychological, symptomatic, andfunctional status of patients with newly diagnosed angina.

Car drivingIn most countries, patients with stable angina are permittedto drive except for commercial public transport or heavyvehicles. Stressful driving conditions should be avoided.

Sexual intercourseSexual intercourse may trigger angina. Common sense willdictate that this should not be too physically or emotionallydemanding. Nitroglycerin prior to intercourse may behelpful. Phosphodiesterase (PGE5) inhibitors such as sildena-fil, tadafil, and vardenafil, used in the treatment of erectiledysfunction, may bestow benefits in terms of exercise dur-ation and can be safely prescribed to men with CAD butshould not be used in those receiving long-acting nitrates.376

The patient must be informed about the potentially harmfulinteractions between PGE5 inhibitors and nitrates or NO(nitric oxide) donors.377,378

EmploymentAn assessment should always be made of the physical andpsychological factors involved in an affected subject’swork (including housework). Patients should, if possible,be encouraged to continue in their occupation, with appro-priate modifications, if necessary.

Pharmacological treatment of stableangina pectoris

The goals of pharmacological treatment of stable anginapectoris are to improve quality of life by reducing the sever-ity and/or frequency of symptoms and to improve the prog-nosis of the patient. Measures of quality of life reflectdisease severity and carry prognostic information if properlyassessed.379 When selecting evidence-based strategies forpharmacological prevention of cardiac complications anddeath, one should consider the often benign prognosis ofthe patient with stable angina pectoris. Pharmacotherapyis a viable alternative to invasive strategies for the treat-ment of most patients with stable angina pec-toris51,290,380,381 and was actually associated with fewercomplications than surgery or PCI during a 1-year follow-upof the MASS-II study.382 An invasive treatment strategy may

26 ESC Guidelines

be reserved for patients at high risk or patients with symp-toms that are poorly controlled by medical treatment.290

The intensity of preventive pharmacotherapy should be tai-lored to the individual risk of the patient, keeping in mindthe relatively low risk of many patients with stable anginapectoris.

Pharmacological therapy to improve prognosisCo-existing disorders such as diabetes and/or hypertensionin patients with stable angina should be well controlled, dys-lipidaemia should be corrected, and smoking cessationattempted (without or with pharmacological support).Statin and angiotensin-converting enzyme (ACE)-inhibitortreatment may provide protection above that which canbe ascribed to their lipid and blood pressure loweringeffects, respectively, and are discussed separately. Inaddition, antiplatelet treatment should always beconsidered for patients with ischaemic heart disease.Levels of evidence based on prognosis and symptom reliefare provided for the recommended treatments for anginain the treatment algorithm illustrated in Figure 7.

Antithrombotic drugs. Antiplatelet therapy to preventcoronary thrombosis is indicated, due to a favourable ratiobetween benefit and risk in patients with stable CAD.Low-dose aspirin is the drug of choice in most cases,whereas clopidogrel may be considered for some patients.Because of the evolving story of increased cardiovascularrisks with cyclooxygenase (COX)-2 inhibitor or NSAIDtreatment, as well as interactions between NSAIDs andaspirin, these drugs will also be commented upon from thecardiovascular perspective.

Low-dose aspirin. Aspirin remains the cornerstone ofpharmacological prevention of arterial thrombosis and isvery well studied.383–387 Aspirin acts via irreversible inhi-bition of platelet COX-1 and thus thromboxane production,which is normally complete with chronic dosing �75 mg/day.385 The optimal antithrombotic dosage of aspirinappears to be 75–150 mg/day, as the relative risk reductionafforded by aspirin may decrease both below and above thisdose range.387 In agreement with this interpretation, anobservational post hoc analysis of the CURE study found anincreased risk of cardiovascular events with an aspirindosage �200 vs. �100 mg per day (HR 1.23; 95% CI1.08–1.39) in patients with acute coronary syndromes.388

Randomized studies comparing different dosages of aspirinare, however, few.Contrary to the antiplatelet effects, the gastrointestinal

side-effects of aspirin increase at higher doses.385 In a well-conducted observational study, a doubling of peptic ulcerbleeding was observed when the aspirin dose increasedfrom 75 to 160 mg, and another doubling when it increasedto 325 mg/day.389 However, in a meta-analysis of long-termstudies,390 there was no clear dose–response relationshipbetween studies regarding the risk of gastrointestinal haem-orrhage. The incidence of gastrointestinal haemorrhage was2.30% with aspirin at a dosage below 162.5 mg/day vs.1.45% with placebo, relative risk 1.59 (95% CI 1.40–1.81).The relative risk in trials using higher doses (.162.5 mg)was 1.96 (95% CI 1.58–2.43). In this meta-analysis, thelarge US Physicians Health Study (USPHS) with 325 mg onalternate days dominated the low-dose aspirin group,whereas the The Swedish Angina Pectoris Aspirin Trial

(SAPAT) study (75 mg daily) was not included. Variable defi-nitions and reporting of gastrointestinal bleeds mayconfound between-study comparisons of different dosagesof aspirin. Antiplatelet therapy in patients with upper gastro-intestinal bleeding problems is commented upon afterclopidogrel.Intracranial bleeds may increase with all antithrombotic

drugs. The relative risk of suffering an intracranial haemor-rhage increases by 30%,391 but the absolute risk of suchcomplications attributable to antiplatelet drug therapy isless than 1 per 1000 patient-years of treatment with aspirinat doses �75 mg/day.383,385 There is no evidence for a dose-dependence of the risk of intracranial bleeding with aspirin inthe therapeutically effective dose range. In patients withatherosclerotic vascular disease, where the main aetiologyof stroke is ischaemic, the net effect of aspirin treatmentregarding stroke is clearly beneficial.383,385 Thus, thedosage of aspirin should be the lowest effective one inorder to optimize the balance between therapeutic gainsand gastrointestinal side effects during chronic therapy.SAPAT showed a 34% reduction of MI or cardiac death, cor-

responding to an absolute risk reduction (ARR) of 1% peryear, with aspirin 75 mg/day compared with placebo insotalol-treated patients with stable angina pectoris.47

Low-dose aspirin treatment slightly increased the risk ofmajor gastrointestinal haemorrhage (11 vs. 6 cases duringmore than 4000 patient-years of treatment in each group).Treatment was discontinued due to adverse effects in 109aspirin vs. 100 placebo-treated patients.47 Thus, aspirin75 mg/day is both effective and well tolerated in stableangina pectoris. Treatment of a small subgroup of doctorswith angina pectoris with 325 mg aspirin every other day(compared with placebo) resulted in a significant reductionof non-fatal MI in the USPHS.392 Low daily dosing of aspirin(75 mg) is thus well documented in stable angina pectorisand is preferred in order to increase compliance (with aregular daily medication routine) and to reduce risks ofside-effects and interactions.

COX-2 inhibitors and NSAIDs. COX-2 inhibition reduces theproduction of prostacyclin, which has vasodilatory andplatelet-inhibiting effects. Attenuation of prostacyclin for-mation may predispose to elevated blood pressure, acceler-ated atherogenesis, and thrombosis upon plaque rupture.393

The recent withdrawal of rofecoxib (Vioxx), a highly selec-tive COX-2 inhibitor, was caused by findings of an increasedrisk of serious coronary events in a placebo-controlled trialof cancer prevention.394 An increased risk of sufferingfatal or non-fatal MI was also found in a meta-analysis ofother randomized trials with rofecoxib.395 There is also sup-porting evidence for harmful effects of COX-2 inhibitionfrom several observational studies.396 A cancer preventiontrial with celecoxib showed a dose-related increase in therisk of suffering cardiovascular complications, with HRs of2.3 (95% CI 0.9–5.5) and 3.4 (1.4–7.8) for 200 and 400 mgcelecoxib bid, respectively.397 A placebo-controlled studyof parecoxib/valdecoxib (ivþ oral therapy) for the treat-ment of post-operative pain after CABG showed an increasedrisk of suffering cardiovascular events with only 10 days oftreatment with COX-2 inhibition.398 Thus, there are indi-cations from studies with several COX-2 inhibitors thatthey may increase the risk of coronary thrombotic eventsin patient populations with different levels of cardiovascular

ESC Guidelines 27

Figure 7 Algorithm for medical management of stable angina. High-risk candidates for revascularization on prognostic grounds alone should be identified and referred appropriately. (Asterisk) Relative contraindications tobeta-blockade include asthma, symptomatic peripheral vascular disease, and first-degree heart block. (Double dagger) Avoid short-acting dihydropyridine formulations when not combined with beta-blocker. Evidence forprognosis refers to evidence of reduction in CV death or CV death/MI. Evidence for symptoms includes reduction in need for revascularization and hospitalization for chest pain.

28ESC

Guid

elines

risk. In addition, COX-2 inhibition increases the risk of suf-fering stroke, heart failure, and hypertension.399 The useof unopposed COX-2 inhibition (i.e. without effective simul-taneous platelet COX-1 inhibition) should thus be avoided inpatients with stable angina pectoris.Non-selective, reversible COX inhibitors (NSAIDs) can

inhibit thromboxane production and platelet aggrega-tion,400,401 as demonstrated for naproxen.402 However, thereversible NSAIDs rarely inhibit thromboxane production aseffectively as aspirin,385 and it has been shown that ,5%residual COX-1 activity in platelets is sufficient to sustainfull platelet aggregation.403 Cardioprotective effects ofnaproxen treatment have been discussed,404–407 but thebalance of evidence indicates that also non-selectiveNSAIDs may increase the risk of cardiovascular compli-cations.396 It is recommended to primarily use paracetamol.If NSAIDs are needed, they should be used in the lowesteffective doses and for the shortest possible duration. Awarning has also recently been issued by the FDA fornaproxen.408 NSAID treatment should, when this is indicatedfor other reasons, be combined with low-dose aspirin toassure effective platelet inhibition in patients with stableangina pectoris. In such circumstances, ibuprofen shouldbe avoided, as this NSAID prevents aspirin from irreversiblyacetylating the COX-1 enzyme of platelets, as maynaproxen.409,410 Diclofenac is a relatively COX2-selectiveNSAID and, therefore, a poor platelet inhibitor, but doesnot interfere with the antiplatelet effects of aspirin andmay be used in combination with aspirin.411

Clopidogrel. Clopidogrel and ticlopidine are thienopyridineswhich act as non-competitive ADP receptor antagonists andwhich have antithrombotic effects similar to aspirin.385

Ticlopidine efficacy has mainly been documented in strokeand PCI385,387 and has been replaced by clopidogrel due tothe risk of neutropenia and thrombocytopenia and moresymptomatic side-effects with ticlopidine. The main studydocumenting clopidogrel use in stable CAD is CAPRIE,412

which included three equally large groups of patients withprevious MI, previous stroke, or peripheral vascular disease(PVD).412 When compared with aspirin 325 mg/day, whichmay be less effective than 75 mg/day (see Figure 7 inCollaborative Meta-analysis of Randomized Trials387), clopi-dogrel 75 mg/day was slightly more effective (ARR 0.51%per year; P ¼ 0.043) in preventing cardiovascular compli-cations in high-risk patients.412 When comparing outcomesin the three subgroups of patients enrolled in CAPRIE, thebenefit with clopidogrel appeared in the PVD subgrouponly.412 Gastrointestinal haemorrhage was only slightly lesscommon with clopidogrel compared with aspirin treatment(1.99 vs. 2.66% during 1.9 years of treatment), despite therelatively high aspirin dose.412 The benefit of clopidogrelmay have been over-estimated because the dose of aspirinwith which it was compared (325 mg) may not be the mosteffective dose. The CAPRIE study did not include patientswith aspirin intolerance, and we do not know the risk of gas-trointestinal bleeding during clopidogrel compared withplacebo treatment. Clopidogrel is more expensive thanaspirin, but may be considered in aspirin-intolerant patientswith significant risks of arterial thrombosis. Gastrointestinalintolerance may, however, be handled differently (discussedsubsequently). After coronary stenting, an acute coronarysyndrome, or an ST-elevation MI, clopidogrel may be

combined with aspirin during a finite period of time, butcombination therapy is currently not warranted in stableangina pectoris. Clopidogrel treatment increases the riskof severe bleeding in connection with CABG surgery.413

One much discussed reason for variability of antiplateletresponses to clopidogrel is drug–drug interactions, as clopi-dogrel forms its active metabolite(s) via CYP3A4-mediatedmetabolism. A study by Lau et al.414 showed that atorvasta-tin, but not pravastatin, dose-dependently inhibited theeffect of clopidogrel on ADP-mediated platelet activation.The study also showed the expected interactions betweenclopidogrel and antibiotics that inhibit (erythromycin andtroleandomycin) or induce (rifampicin) CYP3A4.414 Anotherstudy with clopidogrel maintenance treatment found nointeraction with low-dose atorvastatin (10 mg daily) treat-ment.415 The short-term effects of a 300 mg loading doseof clopidogrel in connection with PCI may416 or may not417

be attenuated by co-treatment with lipophilic statins (ator-vastatin, simvastatin, and lovastatin). The effects of a600 mg loading dose appear to be unaffected by treatmentwith atorvastatin or simvastatin.418,419 Observational posthoc analyses of outcomes among patients receiving mainten-ance co-treatment with clopidogrel and interacting statinhave not shown differences in outcome, but there are noproperly designed prospective studies that address theissue. Data from the large GRACE registry indicate thatstatin treatment has additional benefit to those of clopidogreltreatment, as might be expected.420 Thus, the literature onstatin–clopidogrel interactions is inconsistent, and theimportance of interactions between maintenance therapywith lipophilic statins and clopidogrel is at present not known.

Antiplatelet therapy in patients with gastrointestinalintolerance to aspirin. Gastrointestinal haemorrhages mayincrease with any antiplatelet treatment, but the size ofthis effect with clopidogrel is not known in the absence ofdata from placebo-controlled trials. It has been speculatedthat antiplatelet treatment interferes with the normalwound healing process which limits the progression of sub-clinical and rather common (2% per month without anytreatment) gastric erosions, due to reduced release of plate-let stored growth factors such as VEGF.421 In addition, aspirincauses dose-related gastric mucosal damage which mayincrease the incidence and severity of erosions. Upper gas-trointestinal bleeding due to aspirin or NSAID therapy maybe alleviated by inhibiting gastric acid secretion.Eradication of Helicobacter pylori infection, if present,also reduces the risk of aspirin-related gastorintestinalbleeding.422

Among the different acid reducing therapies available,proton pump inibitor (PPI) treatment has been best docu-mented. Thus, 30 mg/day of lansoprazole reduced therecurrence of ulcer complications from 14.8% in theplacebo group to 1.6% (P ¼ 0.008) during a 12-monthfollow-up of gastroduodenal ulcer patients treated with100 mg aspirin after H. pylori eradication.423 A recentstudy showed that the addition of a PPI (esomeprazole40 mg/day) to aspirin (80 mg/day) was better than switchingto clopidogrel for the prevention of recurrent ulcer bleedingin patients with ulcers and vascular disease.424

Dipyridamole and anticoagulants. Dipyridamole is not rec-ommended for antithrombotic treatment in stable anginadue to poor antithrombotic efficacy387 and the risk of

ESC Guidelines 29

worsening anginal symptoms due to coronary steal phenom-ena.425 Anticoagulant drugs (warfarin or thrombin inhibitors),which are an alternative or combined with aspirin in certainhigh-risk patients, such as post-MI, are not indicated inthe general stable angina population without a separateindication such as AF.

Aspirin resistance. Possible problems related to ‘aspirinresistance’ are of considerable interest386,426 and havebeen much discussed. However, the phenomenon is ill-defined and may be characterized by the occurence of car-diovascular events despite therapy (i.e. therapeutic failure)or by resistance to the pharmacological effects of aspirin, asdetermined by various laboratory methods. There iscurrently no ‘gold standard’ with which to evaluate aspirinresistance, and further research is needed beforeconclusions can be drawn and management schemes canbe implemented.385 Thus, aspirin resistance is still amatter for research on how to monitor and manage patientswith insufficient responses to aspirin.427 A similar issue with‘clopidogrel resistance’ is emerging, and it is similarlyunclear how this should be handled.428–430

Lipid-lowering drugs. Statin treatment reduces the risk ofatherosclerotic cardiovascular complications in bothprimary and secondary prevention settings.431 In patientswith atherosclerotic vascular disease, simvastatin432 andpravastatin433,434 reduce the incidence of serious cardiovas-cular complications by some 30%. The Heart ProtectionStudy (HPS)435 and the Prospective Pravastatin PoolingProject (PPPP), which included primary prevention,433

were large enough to show reduced mortality. Subgroup ana-lyses indicate beneficial effects also in diabetic patientswith vascular disease436,437 and benefits of statin therapyhave also been demonstrated in the elderly (.70years).435,438 In diabetic patients without manifest vasculardisease, simvastatin 40 mg/day437 and atorvastatin 10 mg/day439 provided similar primary protection against majorcardiovascular events. Reductions in major cardiovascularevents were also observed in the placebo-controlled Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm(ASCOT-LLA)440 which evaluated atorvastatin treatment inthe primary prevention of CHD in hypertensive patientswith total cholesterol levels �6.5 mmol/L. In addition tothe relatively low cholesterol levels, blood pressurecontrol in the study was excellent, resulting in a lowabsolute risk of cardiac death and MI in this patient popu-lation. Hence, although the relative risk reduction in totalcoronary events was 36%, the ARR with statin treatmentwas only 0.34% per year regarding cardiac death or MI.440

No trial has been performed specifically in patients withstable angina pectoris, but such patients constitutedsignificant proportions of the trials mentioned. In HPS,for example, 41% of patients were post-MI and 24% hadother CAD.Statins lower cholesterol effectively,431 but mechanisms

other than cholesterol synthesis inhibition, such as anti-inflammatory and antithrombotic effects,441–444 may con-tribute to the cardiovascular risk reduction. In patientswith stable angina, it has been shown that 7 days pre-treatment with atorvastatin 40 mg/day compared withplacebo before PCI reduced procedural myocardial injury,as assessed by biochemical markers.445 Such myocardialprotection by short-term, high-dose atorvastatin

treatment may be related to non-lipid effects of the statintreatment. Similar relative benefits of long-term statintherapy have been observed in patients with different pre-treatment levels of serum cholesterol, even in the ‘normal’range.433,435,439 Thus, recommendations to treat withstatins may be guided as much by the patients level ofcardiovascular risk as by the cholesterol level (within thenormal to moderately elevated range). As for blood pressure(discussed subsequently), the risk associated with choles-terol increases log-linearly from low normal levels,431 andit is therefore difficult to evaluate the relative importancesof cholesterol lowering and other effects of statin treatmentfor the treatment benefits observed. A recent meta-analysisof the effects of different lipid-lowering therapies on mor-tality concluded that statins and n-3 fatty acids reducedmortality, whereas fibrates, resins, niacin, and dietaryinterventions failed to do so; a tendancy towards reducedcardiac mortality was counterbalanced by an increase innon-cardiac mortality in the fibrate trials.364

Current European Prevention guidelines suggest a targetvalue of ,4.5 mmol/L (175 mg/dL) for total cholesteroland 2.5 mmol/L (96 mg/dL) for LDL cholesterol in patientswith established CHD or even those who remain at persist-ently high multifactorial risk (.5% risk of fatal cardiovascu-lar events over 10 years). However, several studies haveshown that C-reactive protein levels predict beneficial out-comes during statin therapy as well do cholesterol levels andthat these two markers of statin responsiveness are addi-tive.444 Such analyses of clinical trial data suggest thatcholesterol-independent effects of statin therapy may beof clinical importance. Thus, patient selection based oncholesterol levels and therapy solely directed at cholesterolgoals may not fully exploit the benefit of statin therapy.Statin therapy should always be considered for patientswith stable CAD and stable angina, based on their elevatedlevel of risk and evidence of benefit of cholesterol loweringwithin the normal range.446 Therapy should aim at statindosages documented to reduce morbidity/mortality in clini-cal trials. If this dose is not sufficient to achieve the targettotal cholesterol and LDL levels as mentioned above, thedose of statin therapy may be increased as tolerated toachieve the targets. The daily statin dosages with soliddocumentation in the above-mentioned studies are simvas-tatin 40 mg, pravastatin 40 mg, and atorvastatin 10 mg.Recently, high-dose atorvastatin treatment (80 mg daily)has been shown to reduce the risk of cardiovascular eventswhen compared with 10 mg atorvastatin or simvastatin�24 mg in patients with stable CAD.447,448 The increasedefficacy of high-dose atorvastatin treatment wasaccompanied by six-fold increase (from 0.2 to 1.2%;P , 0.001) in enzymatic signs of liver damage, but no dis-cernible increase in myalgia.447 High-dose atorvastatintherapy should be reserved for high-risk patients.

Statin treatment is associated with few side effects, butskeletal muscle damage (symptoms, CK elevations, and,rarely, rhabdomyolysis) may occur, and liver enzymesshould be also monitored after initiation of therapy.Gastrointestinal disturbances may limit the dosage. Ifstatins are poorly tolerated at high doses, or lipid controlis not achieved with the highest statin dose, reduction ofthe statin dose and the addition of the cholesterol absorp-tion inhibitor, ezetimibe, may afford adequate reductionof cholesterol.449 Effects on morbidity and mortality of

30 ESC Guidelines

such combination treatment have, however, not yet beendocumented.Lipid-modifying drugs other than statins, e.g. fibrates,

resins, or prolonged release nicotinic acid, and their combi-nations with statins and other hypolipidaemics may beneeded to control the lipid levels among patients withsevere dyslipidaemia. This is especially true of those withlow levels of HDL cholesterol and high triglycer-ides.431,450,451 However, benefits of gemfibrozil treatmentin the VA-HIT study were primarily found among men withinsulin resistance.452 The combination of fibrates withstatin therapy increases the risk of associated myopathy,but fenofibrate has been recently shown not to interferewith the catabolism of statins and is therefore less likelyto increase the risk of myopathy when combined with mod-erate doses of statins.453,454 Fibrate therapy was not associ-ated with reduced total deaths in the meta-analysis ofStuder et al.364 Similarly, the recently published FIELDtrial, comparing fenofibrate and placebo in 9795 patientswith type 2 diabetes, found no mortality benefit and no sig-nificant reduction of the primary combined endpoint of cor-onary death and non-fatal MI.455 Thus, gemfibizol treatmentmay be considered in high-risk patients with low HDL choles-terol, but there is little support for a more widespread useof fibrates. Torcetrapib is a new agent which has beenshown to raise HDL effectively,456 but as yet there is insuffi-cient evidence to make universal recommendations regard-ing target HDL or triglyceride levels to be achieved bypharmacotherapy in the general population with angina.However, adjunctive therapy to statin therapy may be

considered on an individualized basis in patients who havesevere dyslipidaemia and remain at high risk after conven-tional measures (estimated cardiovascular mortality .2%per annum).

ACE-inhibitors. ACE-inhibitors are well established for thetreatment of hypertension and heart failure, but have notbeen shown to confer better overall protection against thecardiovascular complications in hypertension, comparedwith that afforded by other antihypertensive drugs.457–459

ACE-inhibitors or angiotensin receptor blockers (ARBs) arerecommended for the treatment of diabetic patients withmicroalbuminuria to prevent progression of renal dysfunc-tion, and as first-line agents to treat blood pressure indiabetic patients.286,370

Because of observed reductions in MI and cardiac mor-tality in trials of ACE-inhibitors for heart failure andpost-MI, ACE-inhibitors have also been investigated as sec-ondary preventive therapy for patients with coronarydisease without heart failure.252,460,461 The HOPE studyincluded high-risk patients with established CVD (coronaryor non-coronary) or diabetes, and at least one other riskfactor, and randomized them to treatment with ramipril orplacebo for 5 years.460 The EUROPA study included patientswith stable CAD, with a broad range of risk but without clini-cal heart failure, who were randomized to treatment withperindopril or placebo for 4.2 years.461 The PEACE studyincluded patients with stable CAD without heart failurewho were treated with trandolapril or placebo for 4.8years.252 As shown in Figure 1, the annual cardiovascularmortality rates in the placebo groups ranged from 0.8%(PEACE) to 1.6% (HOPE). The differences in cardiovascularrisk were associated with differences in therapy at baseline.

The relative risk reductions for composite primary end-points were in the order of 20% in the HOPE and EUROPAstudies, whereas the PEACE study found no significant riskreduction with ACE-inhibition. The results of the threestudies are unfortunately not directly comparable due todifferent selections of endpoints. Regarding reduction ofthe risk for cardiovascular death, HOPE reported a relativerisk reduction of 26% (95% CI 13–36), EUROPA 14% (95% CI23 to 28), and PEACE 5% (95% CI 219 to 24). The greatestrelative risk reduction in HOPE was seen for stroke (RR0.68; 95% CI 0.56–0.84), which was not reported in EUROPAbut tended to be reduced in PEACE (HR 0.76; 95% CI0.56–1.04). The PEACE investigators also reported norisk reduction when using the combined endpoints ofHOPE (RR 0.93; 95% CI 0.81–1.07) and EUROPA (RR 0.96;95% CI 0.83–1.12), respectively.252 All three studies reportedsignificant reductions of heart failure with ACE-inhibitortreatment.Treatment benefits with ACE-inhibition were thus smaller

in PEACE than in HOPE or EUROPA. One possible explanationfor this difference in outcomes might be differencesbetween the three ACE-inhibitors and/or the relativedosages used. However, the dosage of trandolapril used inPEACE was associated with a significant 25% reduction ofcardiovascular death and a 29% reduction of severe heartfailure, but a lesser decrease in non-fatal MI (214%, NS) inconsecutively enrolled post-MI patients with LV dysfunctionin the TRACE study.462 Baseline blood pressure was lower(133/78 mmHg) in the PEACE population than in either ofthe other two studies. The rates of previous revasculariza-tion ranged from 44% (HOPE) to 72% (PEACE), and drugtherapy at baseline differed between the studies.Lipid-lowering therapy was received by only 29% of patientsin HOPE compared with 70% in PEACE; the correspondingfigures were 76 vs. 96% for antithrombotic drug treatmentand 40 vs. 60% for beta-blocker use. Conversely, calciumchannel blocker (CCB) use at baseline was more commonin the HOPE study. Overall, PEACE patients were at lowerabsolute risk of cardiovascular death than the HOPE orEUROPA patients. These differences in baseline risk andnon-study-related therapy may have contributed impor-tantly to the differences in cardiovascular outcome withACE-inhibitor therapy.The relative effects of ramipril and perindopril on cardio-

vascular outcome were similar in a high-risk population andan intermediate population, respectively, although forobvious reasons, the ARR was greater in the population athighest absolute risk (MICRO-HOPE).463 Pre-defined subgroupanalysis of EUROPA and HOPE according to individual factorsknown to affect risk, such as age, diabetes, prior MI, noncoronary vascular disease, and microalbuminuria, showedrelative benefit of similar magnitude from therapy withACE-inhibitor in almost all subgroups.The blood pressure lowering effects of ACE-inhibition may

have contributed to the beneficial results observed in HOPEand EUROPA. In HOPE, uncontrolled hypertension was anexclusion criterion and mean BP at entry was 139/79 mmHg.460 The overall 3/2 mmHg blood pressure differ-ence between ramipril and placebo treatment460 may havebeen underestimated because of evening dosing of ramipriland office blood pressure measurements the next day. AHOPE substudy with 24 h ambulatory measurementsreported a 10/4 mmHg blood pressure difference during

ESC Guidelines 31

24 h and a 17/8 mmHg difference during the night, com-pared with 8/2 mmHg with office measurements in thesame study.464 In EUROPA, patients with uncontrolled hyper-tension (.180/100 mmHg) were also excluded, and themean blood pressure at baseline was 137/82 mmHg. Theoverall blood pressure difference between perindopril andplacebo treatment was 5/2 mmHg,461 but larger differencesmay have occurred in subgroups of patients. However, analy-sis of the effect of treatment according to tertiles or quar-tiles of baseline blood pressure or fall in blood pressure ontreatment shows significant benefit in all groups, eventhose in the lowest baseline blood pressure or smallestreduction in blood pressure with treatment.465 Benefits ofblood pressure reductions may be expected in subgroupsof patients with clearly elevated blood pressure, but lower-ing blood pressure is associated with a lowering of cardiovas-cular risk also in the ‘normal’ range.466 Thus, it is difficult toseparate blood pressure-related effects from bloodpressure-independent protection afforded by ACE-inhibitionin stable angina pectoris.Further clues regarding the effect of blood pressure low-

ering and ACE-inhibition in stable coronary disease may beobtained from the CAMELOT trial.467 In this study, patientswith angiographic evidence of coronary disease, althoughnot necessarily obstructive, and normal blood pressure(mean BP 129/78 mmHg) were randomized to amlodipine,enalapril, or placebo and followed-up for 2 years. Sixtypercent of the patients had hypertension and they werewell treated in other respects (83% on statins, 75% on a beta-blocker, and 95% on aspirin). Blood pressure reductions(5 mm/2 mm) were almost identical in the two active treat-ment groups. The study was not powered to show effects on‘hard’ endpoints (�670 patients per group), but a ‘post hoc’analysis of the combined endpoint of cardiovascular death,stroke, and MI showed similar non-significant relative riskreductions with enalapril (29%) and amlodipine (30%).Furthermore, an IVUS substudy in 274 patients showed a sig-nificant correlation between the progression of atheromaand the reduction in blood pressure even at this ‘normal’range of blood pressure. The recently presented VALUEstudy, which compared antihypertensive treatment withamlodipine or valsartan in 15 245 patients (46% of whomhad CAD) during 4.2 years, found that blood pressure lower-ing was more important than the type of drug used.468 Thesestudies support the contention that the benefits of loweringblood pressure extend into the ‘normal’ blood pressurerange, as suggested by epidemiological data,466 and thateffects on outcome of blood pressure lowering are similarwith ACE-inhibitors or ARBs when compared with calciumantagonists.457,458 A report from the ASCOT study claimsthat blood pressure alone does not account for differencesin outcome between different blood pressure treatmentregimens, with the combination of CCBs and ACE-inhibitortherapy achieving greater reduction in clinical events thanthe combination of beta-blocker and diuretic.469 However,the accompanying editorial points out that blood pressuredifferences may fully explain the differences in outcomebetween the two groups.470 The benefits of blood pressurelowering in the normal range, are likely to be greatest inthose at highest absolute risk,471 particularly those withestablished vascular disease, but the level of blood pressurebelow which clinically appreciable benefit may be observedhas not been established.

The blood pressure lowering effects of ramipril and peri-ndopril compared with placebo, thus probably contributedto the risk reduction in the HOPE and EUROPA studies, butadditional cardioprotection may also be afforded byACE-inhibitors.441 Furthermore, ACE-inhibition is well estab-lished in the treatment of heart failure or LV dysfunction,472

and in the treatment of diabetic patients with renal involve-ment.370 Thus, it is appropriate to consider ACE-inhibitorsfor the treatment of patients with stable angina pectorisand co-existing hypertension, diabetes, heart failure,asymptomatic LV dysfunction, or post-MI. In angina patients,without co-existing indications for ACE-inhibitor treatmentthe anticipated benefit of treatment (possible ARR)should be weighed against costs and risks for side-effects,and the dose and agent used of proven efficacy for thisindication.

Effects of ARB treatment on prognosis in ischaemic heartdisease are less well studied, but the VALIANT studyshowed similar effects of valsartan and captopril treatmentin post-MI patients with heart failure.473 However, theCHARM-preserved study474 showed no significant benefit ofcandesartan compared with placebo in patients with pre-served ventricular function. Thus, ARB treatment may beappropriate therapy for the treatment of heart failure,hypertension, or diabetic renal dysfunction in patientswith angina when ACE-inhibition is indicated but not toler-ated, but there is no indication for ARB therapy in patientswith preserved ventricular function without diabetes as asecondary preventive agent.

Hormone replacement therapy. Epidemiological evidencesuggested substantial cardiovascular benefits of post-menopausal use of hormone replacement therapy (HRT).More recently, however, properly designed prospective,double-blind, placebo-controlled trials have shown thatHRT with a combination of oral oestrogen/progestinoffered no cardiovascular benefit among women withestablished disease475,476 and that there is an increasedrisk of developing CVD in primary prevention, and also anincreased risk of suffering breast cancer.477 Primaryprevention with unopposed oestrogen therapy in hysterecto-mized women offered no cardiovascular protection.478

New guidelines therefore recommend against routine useof HRT for chronic conditions349 and current users havebeen advised to taper doses downwards towardsdiscontinuation.479

Beta-blockers. The risk of suffering cardiovascular death orMI was reduced by beta-blockers by some 30% in post-MItrials.480 A recent meta-regression analysis of the effectsof different beta-blockers on mortality found non-significantbenefits of acute treatment, but a significant 24% relativerisk reduction in mortality with long-term secondary preven-tive treatment.481 Beta-blockers with intrinsic sympathomi-metic activity appeared to provide less protection, and itwas pointed out that the most frequently prescribedagent, atenolol, had poor documentation regarding mor-tality after MI.481 Also, a recent meta-analysis of atenololtrials in hypertension questioned the prognostic benefitafforded by this drug482 even though beta-blockers as agroup provided similar protection as other antihyperten-sive drugs in previous meta-analyses.457,458 It has beenextrapolated from the post-MI trials that beta-blockersmay be cardioprotective also in patients with stable

32 ESC Guidelines

coronary disease. However, this has not been proven in aplacebo-controlled trial. The beta-blocker trials post-MIwere performed before the implementation of other sec-ondary preventive therapy, such as treatment withstatins and ACE-inhibitors, which leaves some uncertaintyregarding their efficacy on top of a ‘modern’ treatmentstrategy.Large beta-blocker studies in stable angina, the APSIS49

and TIBET48 studies, did not include placebo groups due toconcerns about withholding symptomatic treatment duringlong periods of time. In the APSIS trial, which comprised809 patients with clinically diagnosed stable anginapectoris, and a median follow-up of 3.4 years (.1400patient-years of treatment in each group)49 treatmentwith verapamil SR (240–480 mg/day) was associated with asimilar cardiovascular event rate as treatment with meto-prolol CR (100–200 mg/day). An extended follow-up ofthe APSIS study (to a median of 9.1 years) did not alterthese findings, and showed an excellent prognosis of thestable angina patients, especially female patients withoutdiabetes, compared with their background population.483

In the TIBET trial, which comprised 682 patients withexercise-induced angina pectoris followed during a medianof 2 years (�450 patient-years in each group),48 theeffects of nifedipine SR (20–40 mg bid) did not differ signifi-cantly from those of atenolol (50 mg bid), but combinationof the two drugs tended to be advantageous.A smaller study (�300 patient-years) in patients with CAD

and minimal or no symptoms of angina compared atenololand placebo treatment (the ASIST trial), and showed ahigher incidence of a combined endpoint which includedsymptoms requiring treatment in the placebo group.484

This confirmed the beneficial anti-anginal effects of a beta-blocker, but does not show if treatment alters the prognosisof patients with stable angina pectoris.Beta-1 blockade by metoprolol or bisoprolol have been

shown to effectively reduce cardiac events in patientswith congestive heart failure.485,486 Carvedilol, a non-selective beta-blocker that also blocks alpha-1 receptors,also reduces risk of death and hospitalizations for cardiovas-cular causes in patients with heart failure.487

Calcium channel blockers. Heart rate lowering CCBs mayimprove the prognosis of post-MI patients, as shown in theDAVIT II study for verapamil488 and in a subgroup analysisof patients without signs of heart failure in the MDPITstudy for diltiazem.489 Also, in the INTERCEPT trial therewas a trend towards a reduction in the primary endpointof cardiac death, non-fatal re-infarction and refractoryischaemia, and a significant reduction of the need for revas-cularization among post-MI patients treated with diltiazemcompared with placebo.490 CCBs are also effective antihy-pertensive agents without advantages over other bloodpressure lowering drugs regarding clinical outcomesoverall, but CCB treatment is associated with an increasedrisk of heart failure.457–459

Prognostic documentation in stable CAD has not beenavailable for dihydropyridine CCBs until recently. Oldertrials of short-acting nifedipine showed no benefit regardinghard endpoints among patients with CAD, and even anincreased risk of dying with high doses of the drug.491 Thissparked an intense ‘calcium antagonist debate’ whichpointed out the inappropriateness of treatment with short-

acting vasodilator drugs such as dihydropyridine CCBs. Ameta-analysis of the safety of nifedipine in stable anginapectoris suggested that the drug was safe.492

The recently published ACTION trial493 (Table 5), whichcompared treatment with long-acting nifedipine andplacebo during 4.9 years of follow-up in 7665 patients withstable angina pectoris, is adequately powered for assess-ments of morbidity and mortality. The ACTION trialshowed no benefit of treatment with long-acting nifedipinecompared with placebo with regard to composite endpointsincluding death, MI, refractory angina, debilitating stroke,and heart failure. Nifedipine treatment tended to increasethe need for peripheral revascularization (HR 1.25;P ¼ 0.073), but reduced the need for coronary bypasssurgery (HR 0.79; P ¼ 0.0021). The authors concludedthat nifedipine treatment is safe and reduces the needfor coronary interventions,493 but has not been shown tohave beneficial effects on hard endpoints such as deathand MI.A major drawback with the ACTION trial is the liberal

inclusion of patients with high blood pressure, as the bloodpressure lowering effects of nifedipine compared withplacebo would be expected to provide health benefits unre-lated (or in addition) to those possibly afforded by the anti-ischaemic or other effects of calcium antagonism. Thus,ACTION included patients with blood pressures ,200/105 mmHg, and 52% of the patients had blood pressures�140/90 mmHg at baseline, even though the averageblood pressure was 137/80 mmHg. The proportion withblood pressure �140/90 mmHg was reduced to 35% in thenifedipine group and 47% in the placebo group,493 indicatingthat attempts to achieve similar blood pressure controlamong all participants in the study were insufficient. Onaverage, nifedipine treatment caused a slight, but signifi-cant and sustained elevation of heart rate by approximately1 bpm, and reduced blood pressure by �6/3 mmHg.Subgroup analysis of the ACTION study showed significantbenefit of nifedipine treatment among patients with elev-ated blood pressure at baseline but a tendency towardsunfavourable results among those who had blood pressuresbelow 140/90 mmHg. A 6 mmHg reduction of systolic bloodpressure would be expected to reduce major cardiovascularevents by some 25% according to the meta-regressionanalysis of Staessen et al.,458 and this effect should notbe restricted to clearly hypertensive patients.466 Thus,the findings of ACTION may not be compatible with thebenefits one might expect due to the reduction of bloodpressure.The CAMELOT study467 compared treatment with amlodi-

pine, enalapril, or placebo in 1991 patients with stableCAD and normal blood pressure during 2 years of follow-up.As discussed earlier, amlodipine and enalapril treatmentlowered blood pressure equally and seemed to reduce theincidence of ‘hard’ endpoints similarly, although theseresults were not significant.The abovementioned APSIS49 and TIBET48 studies were not

placebo-controlled or ‘powered’ to determine effects onmortality, but show no major differences between beta-blockers and CCBs with regard to cardiovascular morbidityand mortality during long-term treatment of stable anginapectoris. A meta-analysis of 72 trials comparing calciumantagonists and beta-blockers in stable angina pectoris indi-cated similar outcomes with the two drug classes.494

ESC Guidelines 33

However, the mean duration of the studies in thismeta-analysis was only 8 weeks. A meta-analysis restrictedto six larger trials reached a similar conclusion.157

To conclude, there is no evidence to support the use ofCCBs for prognostic reasons in uncomplicated stableangina, although heart rate lowering CCBs may be used asan alternative to beta-blockers post-MI in patients withoutheart failure who do not tolerate beta-blockers.Recommendations for pharmacological therapy to

improve prognosis in patients with stable anginaClass I

(1) Aspirin 75 mg daily in all patients without specific con-traindications (i.e. active GI bleeding, aspirin allergy,or previous aspirin intolerance) (level of evidence A)

(2) Statin therapy for all patients with coronary disease(level of evidence A)

(3) ACE-inhibitor therapy in patients with coincident indi-cations for ACE-inhibition, such as hypertension,heart failure, LV dysfunction, prior MI with LV dysfunc-tion, or diabetes (level of evidence A)

(4) Oral beta-blocker therapy in patients post-MI or withheart failure (level of evidence A)

Class IIa

(1) ACE-inhibitor therapy in all patients with angina andproven coronary disease (level of evidence B)

(2) Clopidogrel as an alternative antiplatelet agent inpatients with stable angina who cannot take aspirin(e.g. aspirin allergic) (level of evidence B)

(3) High dose statin therapy in high-risk (.2% annual CVmortality) patients with proven coronary disease(level of evidence B)

Class IIb

(1) Fibrate therapy in patients with low HDL and hightriglycerides who have diabetes or the metabolicsyndrome (level of evidence B)

(2) Fibrate or nicotinic acid as adjunctive therapy to statinin patients with low HDL and high triglycerides at highrisk (.2% annual CV mortality) (level of evidence C)

Pharmacological treatment of symptoms and ischaemiaSymptoms of angina pectoris and signs of ischaemia (alsosilent ischaemia) may be reduced by drugs that reducemyocardial oxygen demand and/or increase blood flow tothe ischaemic area. Commonly used anti-anginal drugs arebeta-blockers, calcium antagonists, and organic nitrates.

Short-acting nitrates. Rapidly acting formulations of nitro-glycerin provide effective symptom relief in connectionwith attacks of angina pectoris, and may be used for ‘situa-tional prophylaxis’.157,377,495,496 The pain relieving and anti-ischaemic effects are related to venodilatation and reduceddiastolic filling of the heart (reduced intracardiac pressure),which promotes subendocardial perfusion. Coronaryvasodilatation and antagonism of coronary vasospasm maycontribute. Nitrate tolerance (see below) blunts responsesto short-acting nitroglycerin, and should be avoided.There is marked first-pass metabolism of orally adminis-

tered nitroglycerin. Absorption via the oral mucosa is rapidand by-passes the liver, leading to increased bioavailability.Thus, rapid and efficient symptom relief by nitroglycerinmay be achieved with sublingual or buccal tablets, or

an oral spray. Buccal tablets have a longer duration ofaction and may be useful for situational prophylaxis.Nitroglycerin tablets decay when exposed to air, andopened containers should be discarded within 3 months;spray formulations are stable.

Nitroglycerin causes dose-dependent vasodilator side-effects, such as headache and flushing. Overdosing maycause postural hypotension and reflexogenic cardiac sym-pathetic activation with tachycardia, leading to ‘paradoxi-cal’ angina. An attack of angina that does not respond toshort-acting nitroglycerin should be regarded as a possibleMI. Thus, patients should be carefully instructed abouthow to use short-acting nitroglycerin. Short-acting nitrateconsumption is a simple and good measure of treatmenteffects with other anti-anginal drugs.

Long-acting nitrates. Treatment with long-acting nitratesreduces the frequency and severity of anginal attacks, andmay increase exercise tolerance.157,377,495,496 Long-actingnitrate treatment is only symptomatic, as studies after MIhave failed to show prognostic benefit of such treat-ment.497,498 Side effects are mainly related to vasodilata-tion, i.e. headaches and flushing, as described earlier.

Several long-acting nitrates are available. Isosobidedinitrate (ISDN) has an intermediate duration of action,and requires more than once daily dosing. Isosorbide-5-mononitrate (ISMN) is supplied in various formulationsthat provide extended action of a suitable duration (seebelow). Nitroglycerin patches for transdermal treatmentallow full control of the duration of action, but are moreexpensive than ISDN or ISMN.

Nitrate tolerance may develop when nitrate levels arecontinuously maintained above a certain threshold level,and results in poorer protection against angina attacks andresistance to the pain relieving effects of short-acting nitro-glycerin. Thus, patients treated with long-acting nitratesshould have a ‘nitrate-free’ interval each day to preservethe therapeutic effects. This may be achieved with appro-priate timing of doses of intermediate acting ISDN or withformulations of ISMN that provide a suitable plasma concen-tration profile. Continuous transdermal nitroglycerintherapy is not effective and patients should remove thepatches during part of the day or at night to achieve thenitrate-free interval; a decreased anginal threshold andrebound angina may, however, occur when patches areremoved.499–501 Transdermal nitroglycerin has been moreclearly associated with rebound ischaemia than oral long-acting nitrate treatment.495

Beta-blockers. Beta-blockers are well documented for theprevention of anginal symptoms and ischaemia.157,377,502,503

They reduce oxygen demand by reducing heart rate andcontractility, and by reducing blood pressure. Resting andexercise heart rate will be reduced by most beta-blockersexcept those with partial agonist activity where only the exer-cise heart rate is reduced. Perfusion of ischaemic areas maybe improved by prolonging diastole (i.e. the perfusiontime), and by ‘reverse coronary steal’ due to increased vascu-lar resistance in non-ischaemic areas.425 Beta-blockers arealso well established in the treatment of hypertension.286

Beta-1 selective antagonists are as effective as non-selective antagonists,157 indicating that the beta-1 selectivesympathetic neurotransmitter, noradrenaline, is the primarybeta-adrenergic target for inhibition. Beta-1 selective

34 ESC Guidelines

agents are preferred due to advantages concerningside-effects and precautions compared with non-selectivebeta-blockers.157,377 Commonly used beta-1 blockers withgood documentation as anti-anginal drugs are metoprolol,atenolol, and bisoprolol. The anti-anginal and anti-ischaemiceffects are related to the degree of cardiac beta-1 adreno-ceptor blockade, i.e. to the plasma concentration of thedrug, whereas the blood pressure lowering effect in hyper-tension is not. To achieve 24 h efficacy a beta-1 blockerwith a long half-life (e.g. bisoprolol) or a formulation provid-ing an extended plasma concentration profile (e.g. metopro-lol CR) may be used. For atenolol (with a plasma half-life of6–9 h), twice daily dosing may be better, but increasing thedose also extends the duration of action. Target doses forfull anti-anginal effects are: bisoprolol 10 mg od, metoprololCR 200 mg od, atenolol 100 mg/day od (or 50 mg bid). Thedegree of beta-blockade may be assessed by exercisetesting. Beta-blockers are effective anti-anginal drugs whichincrease exercise tolerance, and decrease symptoms andshort-acting nitrate consumption.157,377,502,503 However,symptoms may increase on beta-blockade in patients withvasospastic angina.Side-effects of beta-blockade include cold extremities

and symptomatic bradycardia, both of which are relatedto cardiac inhibition, and increased respiratory symptomsin asthma/COPD (less common with beta-1 selectiveagents). Beta-blockers may cause fatigue, but only 0.4% ofpatients in trials discontinued treatment for this reason.504

Similarly, depression was not increased among beta-blockertreated patients, and sexual dysfunction was only found in5/1000 patient-years of treatment (leading to discontinu-ation in 2/1000).505 Quality of life, which has been exten-sively studied in the treatment of hypertension, is wellpreserved with beta-blocker treatment of hypertensivepatients,505,506 but this has not been systematicallystudied in patients with stable angina.379 Psychosocial vari-ables reflecting quality of life were similarly influenced bymetoprolol and verapamil treatment in the APSIS study.49

Thus, the side-effect profile of beta-blockade may not beas unpalatable to patients as commonly perceived.

Calcium channel blockers. CCBs are also well establishedanti-anginal agents.157,377,467,502,503 This is a heterogeneousclass of drugs which dilatate coronary and other arteries byinhibiting calcium influx via L-type channels. Non-selectiveor heart rate lowering CCBs (verapamil and diltiazem) alsoto some degree reduce myocardial contractility, heartrate, and A-V nodal conduction.157,377 Even vasoselectivedihydropyridine CCBs (e.g. nifedipine, amlodipine, and felo-dipine) may cause some cardiodepression, but this is coun-teracted by reflexogenic cardiac sympathetic activationwith slight increases in heart rate which subside over time.However, signs of sympathetic activation may be seen evenafter months of treatment with a dihydropyridine CCB.507

Long-acting CCBs (e.g. amlodipine) or sustained releaseformulations of short-acting CCBs (e.g. nifedipine, felodi-pine, verapamil, and diltiazem) are preferred, to minimizefluctuations of plasma concentrations and cardiovasculareffects.508 Side effects are also concentration-dependent,and mainly related to the arterial vasodilator responses(headache, flushing, and ankle oedema). These effects aremore pronounced with dihydropyridine CCBs. Verapamilmay cause constipation.

The anti-anginal effects of CCBs are related to decreasedcardiac work due to systemic vasodilatation, as well as coro-nary vasodilatation and counteraction of vasospasm.157,377

CCBs are especially effective in patients with vasospastic(prinzmetal) angina, but in some patients CCBs may,however, increase ischaemia.509

The CAMELOT study467 showed that the anti-anginaleffects of amlodipine compared with placebo treatment sig-nificantly reduced hospitalization for angina, as well as theneed for revascularization during a 2-year follow-up.Enalapril treatment was not associated with similar effectson ischaemia-related outcomes. In the CAPE study,510 treat-ment with amlodipine compared with placebo resulted in amodest, but significant further reduction of ischaemia onHolter monitoring (placebo effects were rather pronounced)after 7 weeks of treatment. The patients reported greaterreductions of anginal attacks (70 vs. 44%) and a more pro-nounced reduction of nitroglycerin consumption (67 vs.22%) during week 10 of amlodipine compared with placebotreatment. The side-effect profile of amlodipine was favour-able in both CAMELOT and CAPE. In the ACTION study,although not associated with a reduction in the primary end-point (death, acute MI, refractory angina, new overt heartfailure, debilitating stroke, and peripheral revasculariza-tion), nifedipine therapy was associated with reducedneed for coronary bypass surgery (HR 0.79, P ¼ 0.002).493

The anti-anginal and anti-ischaemic effects of CCBs areadditive to those of beta-blockers in many, but not allpatients. Dihydropyridine CCBs are suitable for combinationwith beta-blockers, which counteract the reflexogeniccardiac sympathetic activation. Heart rate lowering CCBsmay cause conduction disturbances in predisposed patientstreated with beta-blockers. All CCBs may precipitate heartfailure in predisposed patients. Attempts to use dihydro-pyridine CCBs for vasodilator treatment of heart failurehave not been successful. However, amlodipine may beused for the treatment of angina in patients with compen-sated heart failure if not controlled by other therapy (i.e.nitrates, beta-blockers).511

Comparison of beta-blocker and calcium antagonist (CCB)treatment in stable angina. The IMAGE study512 comparedpatients with stable angina treated with metoprolol CR200 mg od or nifedipine SR 20 mg bid during 6 weeks (140patients in each group). Both metoprolol and nifedipine pro-longed exercise tolerance over baseline levels, with greaterimprovement in patients receiving metoprolol (P, 0.05).Responses to the two drugs were variable, and were difficultto predict. In the APSIS study, treatment with verapamil SRfor 1 month was slightly more effective than metoprolol CRin increasing exercise tolerance.513 However, althoughexercise-induced ischaemia was predictive of cardiovascularevents in the study,513 short-term treatment effects onexercise-induced ischaemia did not independently predictimprovement in long-term outcome. This highlights theimportant difference between treatment of symptomsand ischaemia and treatment aimed prognosis. Severity ofischaemia on baseline assessment acts as a marker of theunderlying severity of coronary disease. But it is the severityof disease which influences the likelihood of plaque destabi-lization, and the propensity to and severity of thromboticcomplications if and when plaque becomes unstable,

ESC Guidelines 35

factors which are not modified by traditional anti-ischaemicagents.The TIBBS study514 showed anti-ischaemic and anti-anginal

effects of both bisoprolol and nifedipine, but bisoprolol wasclearly more effective. The TIBET study compared theeffects of atenolol, nifedipine, or their combination onexercise-induced ischaemia and the total ischaemic burdenin a double-blind, parallel group design. Both medications,alone and in combination, caused significant improvementsin exercise parameters and significant reductions in ischaemicactivity during daily activities when compared with placebobut there were no significant differences between groupsfor any of the measured ischaemic parameters. There weresignificantly more withdrawals because of side-effects inthe nifedipine group compared with the atenolol and thecombination groups.48,515 Meta-analyses comparing effectsof beta-blockers and CCBs in stable angina pectoris indicatethat beta-blockers are more effective than CCBs in reducinganginal episodes,494 but that effects on exercise toleranceand ischaemia of the two drug classes are similar.157,494

Thus, in the absence of prior MI, the available datasuggest that the choice between a beta-blocker and a CCBfor anti-anginal treatment may be guided by individualtolerance and the presence of other disease andco-treatment. If these factors are equally weighted, abeta-blocker is recommended as the first choice.

Comparison of nitrates with beta-blockers or CCBs. Thereare relatively few studies comparing anti-anginal and anti-ischaemic effects of long-acting nitrates with beta-blockersor CCBs, and there is no documentation concerning possibleeffects of nitrates on morbidity in stable angina pectoris.494

There were non-significant trend towards less nitroglycerinuse with beta-blockers, and fewer angina episodes perweek with CCBs compared with long-acting nitrates in themeta-analysis by Heidenreich et al.494 Thus long-actingnitrates have no overall therapeutic advantages over beta-blockers or CCBs.

Potassium channel openers. The principal agent in this class,nicorandil, has a dual mechanism of action, and is a potass-ium channel activator with a nitrate moiety and nitrate likeeffects.516 Nicorandil is administered at a usual dose of20 mg bid for the prevention of angina. Tolerance to theanti-anginal effect may develop with chronic dosing,517

but cross-tolerance with nitrates does not seem to be aproblem.516 In addition to its anti-anginal properties,nicorandil is thought to have cardioprotective proper-ties.516,518 The Impact Of Nicorandil in Angina (IONA) trialshowed a significant reduction of major coronary events instable angina patients treated with nicorandil comparedwith placebo as add-on to conventional therapy.254

However, the result was driven by effects of nicorandil on‘hospital admission for cardiac chest pain’, and the riskreduction regarding cardiac death or non-fatal MI during1.6 years of treatment was non-significant;254 thus thevalue of the treatment effect has been argued.518

Nicorandil is not available in all countries.

Other agents. Sinus node inhibitors, such as ivabradine, actby selectivity inhibiting the cardiac pacemaker current If,and have negative chronotropic effects both at rest andduring exercise. If inhibition has proven anti-anginal effi-cacy461,519,520 and ivabradine may be used as an alternative

agent in patients who do not tolerate beta-blockade. It hasbeen licenced by the EMEA for this purpose.

Metabolically acting agents protect from ischaemia byincreasing glucose metabolism relative to that of fattyacids. Trimetazidine and ranolazine are both considered asmetabolic anti-anginal drugs. However, ranolazine has alsomore recently been shown to be an inhibitor of the latesodium current,521 which is activated in case of ischaemia,leading to calcium overload of the ischaemic myocardium,decreased compliance, increased LV stiffness, and com-pression of the capillaries. The inhibition of the latesodium current by ranolazine reverses these effects, andprevents calcium overload, and the subsequent conse-quences thereof.522,523

Both trimetazidine524–526 and ranolazine527,528 have beenshown to have anti-anginal efficacy. They may be used incombination therapy with haemodynamically actingagents, as their primary effect is not through reduction inheart rate or blood pressure. Trimetazidine has been avail-able for several years, but not in all countries. Ranolazine,although under intensive investigation is not yet licencedfor use by the EMEA. Whether these drugs influence theprognosis of patients with stable angina has not beendetermined.

Molsidomine is a vasodilator with an action similar to thatof organic nitrates and in the appropriate dosage is aneffective anti-ischaemic and anti-anginal agent.529 It is notavailable in all countries.

Recommendations for pharmacological therapy. Anti-anginal drug treatment should be tailored to the needs ofthe individual patient, and should be monitored individually.Short-acting nitrate therapy should be prescribed for allpatients for immediate relief of acute symptoms as toler-ated. Although different types of drugs have been shownto have additive anti-anginal effects in clinical trials, thismay not necessarily be so in the individual patient. Moreintense anti-anginal treatment may also cause problems,as it has been shown that three anti-anginal drugs mayprovide less symptomatic protection than two drugs.530,531

Thus, the dosing of one drug should be optimized beforeadding another one, and it is advisable to switch drug com-binations before attempting a three drug regimen. Pooradherence is always a factor to consider when drugtherapy is unsuccessful.

An algorithm depicting the strategy for medical manage-ment of stable angina, if revascularization is not considerednecessary after initial evaluation and risk stratification,includes treatments aimed at improving prognosis and symp-toms and is shown in Figure 7. The following recommen-dations pertain to anti-anginal therapy and the level ofevidence refers to anti-anginal or anti-ischaemic efficacyunless stated otherwise.

Recommendations for pharmacological therapy toimprove symptoms and/or reduce ischaemia in patientswith stable anginaClass I

(1) Provide short-acting nitroglycerin for acute symptomrelief and situational prophylaxis, with appropriateinstructions on how to use the treatment (level ofevidence B)

36 ESC Guidelines

(2) Test the effects of a beta-1 blocker, and titrate to fulldose; consider the need for 24 h protection againstischaemia (level of evidence A)

(3) In case of beta-blocker intolerance or poor efficacyattempt monotherapy with a CCB (level of evidence A),long-acting nitrate (level of evidence C), or nicorandil(level of evidence C)

(4) If the effects of beta-blocker monotherapy are insuffi-cient, add a dihydropyridine CCB (level of evidence B)

Class IIa

(1) In case of beta-blocker intolerance try sinus nodeinhibitor (level of evidence B)

(2) If CCB monotherapy or combination therapy (CCB withbeta-blocker) is unsuccessful, substitute the CCB with along-acting nitrate or nicorandil. Be careful to avoidnitrate tolerance (level of evidence C)

Class IIb

(1) Metabolic agents may be used, where available, asadd-on therapy, or as substitution therapy when con-ventional drugs are not tolerated (level of evidence B)

Consider triple therapy only if optimal two drug regimensare insufficient, and evaluate the effects of additional drugscarefully. Patients whose symptoms are poorly controlled ondouble therapy should be assessed for suitability for revas-cularization, as should those who express a strong prefer-ence for revascularization rather than pharmacologicaltherapy. The ongoing need for medication to improve prog-nosis irrespective of revascularization status, and thebalance of risk and benefit on an individual basis, shouldbe explained in detail. Despite the array of therapeuticoptions outlined, the management of refractory angina con-tinues to pose a challenge, and management options in suchcases are outlined in a separate section below.

Special therapeutic considerations: cardiac Syndrome Xand vasospastic anginaTreatment of Syndrome X. Treatment should focus on sympto-matic relief.532 As nitrates are effective in about half of thepatients,303,532 it is reasonable to start treatment withlong-acting nitrates. If symptoms persist, calcium antagon-ists533 and b-blockers,534 which are beneficial in Syndrome Xpatients, may be added. Although a-adrenergic blockadeincreases vasodilator reserve in patients with Syndrome X,535

a-adrenergic blocking agents are clinically inefficient.536,537

There are reports that other drugs such as nicorandil538 andtrimetazidine539 might be helpful in some patients.ACE-inhibitors540 and statins541 are helpful to reverse

underlying endothelial dysfunction. Thus, these drugsshould be actively considered for patients with Syndrome Xas part of their risk factor management,542 and there aresome data to suggest that ACE-inhibitors and statins mayalso be beneficial in reducing exercise-induced ischaemia inthis population.541,543,544

The challenge of achieving long-lasting therapeutic effectsin patients with Syndrome X requires a multidisciplinaryapproach.545 This might include analgesic interventionusing imipramine546 or aminophylline,547 psychological inter-vention,545 electrostimulation techniques,548 and physicaltraining.549 Some studies of transdermal hormone replace-ment therapy550,551 in post-menopausal patients have

shown an improvement in endothelial function and symp-toms, but in the light of recent trials documenting adversecardiovascular outcomes with the use of HRT, caution isadvised in prescription of HRT for this purpose.Recommendations for pharmacological therapy to

improve symptoms in patients with Syndrome XClass I

(1) Therapy with nitrates, b-blockers, and calcium antag-onists alone or in combination (level of evidence B)

(2) Statin therapy in patients with hyperlipidaemia (levelof evidence B)

(3) ACE inhibition in patients with hypertension (level ofevidence C)

Class IIa

(1) Trial of therapy with other anti-anginals includingnicorandil and metabolic agents (level of evidence C)

Class IIb

(1) Aminophylline for continued pain, despite Class Imeasures (level of evidence C)

(2) Imipramine for continued pain, despite Class Imeasures (level of evidence C)

Treatment of vasospastic angina. Removal of precipitatingfactors such as cessation of smoking is essential.552 Themain elements of drug therapy are nitrates and calciumantagonists. Although nitrates are highly effective in abol-ishing acute vasospasm, they are not as successful in pre-venting attacks of resting angina.340 CCBs are moreeffective in alleviating the signs and symptoms of coronaryspasm and treatment should be aimed at using high doses(up to 480 mg/d verapamil, up to 260 mg/d diltiazem, upto 120 mg/d nifedipine). However, calcium antagonistsachieve a complete resolution of symptoms in only 38% ofpatients.340 In most patients, a combination therapy withlong-acting nitrates and high doses of calcium antagonistswill result in an improvement of symptoms. In patientswith resistant symptoms, addition of a second calciumantagonist of another class may be successful. Medical treat-ment seems to be more effective in women and in patientswith ST-elevation during provocation testing.340

The role of a-blockers is controversial but occasionaltherapeutic benefit has been reported.553 Nicorandil, a pot-assium channel activator, may also be useful in occasionalpatients with refractory vasospastic angina.554 Reports ofsuccess in treating drug-resistant focal vasospasm by coron-ary artery stenting exist,555,556 but this approach is notadvocated for widespread application. CABG is not indicatedbecause spasm distal to the anastomosis may occur.Spontaneous remission of spasmodicity occurs in about

half of western people following medical treatment for atleast 1 year.557 Thus, it is acceptable to taper and discon-tinue treatment 6–12 months after angina has disappearedon drug treatment. If vasospasm occurs in association withsignificant coronary disease, guideline recommendationsfor treatments to improve prognosis and secondary preven-tion should also be adhered to.Recommendations for pharmacological therapy of

vasospastic anginaClass I

ESC Guidelines 37

(1) Treatment with calcium antagonists and if necessarynitrates in patients whose coronary arteriogram isnormal or shows only non-obstructive lesions (level ofevidence B)

Myocardial revascularization

There are two well-established approaches to revasculariza-tion for treatment of chronic stable angina caused bycoronary atherosclerosis: surgical revascularization, coron-ary artery bypass graft (CABG), and percutaneous coronaryintervention (PCI). Currently, both methods are facingrapid development with the introduction of minimally inva-sive and off-pump surgery and drug-eluting stents. As in thecase of pharmacological therapy, the potential objectives ofrevascularization are two-fold, to improve survival or survi-val free of infarction or to diminish, or eradicate symptoms.The individual risk of the patient as well as symptomaticstatus must be a major factor in the decision-makingprocess.

Coronary artery bypass surgeryFavorolo first described the use of saphenous vein to bypassa diseased coronary artery in 1969. Since then CABG hasbecome the most common operation for CAD and one ofthe most commonly performed surgical operations world-wide. There are two main indications for CABG: prognosticand symptomatic. Prognostic benefit of CABG is mainly dueto a reduction in cardiac mortality, as there is less evidencefor reduction in MI.69,290 Evidence of prognostic benefit ofCABG compared with medical therapy has not been demon-strated in low-risk patients (annual mortality ,1%).69 In ameta-analysis of surgical trials comparing CABG withmedical therapy, CABG was shown to improve prognosis inthose at medium to high risk, but even those in themedium risk had a 5-year mortality rate with medicaltherapy of 13.9%, annual mortality 2.8%, which by contem-porary standards appears high. Further observational datafrom the Duke registry confirmed that long-term mortalitybenefit associated with surgery was limited to high-riskgroups.558 Analyses of observational and randomized con-trolled trial data have revealed that the presence of specificcoronary artery anatomy is associated with a better progno-sis with surgery than with medical treatment.69,288 Suchdisease includes the following:

(1) significant stenosis of the left main (LM) stem(2) significant proximal stenosis of the three major coron-

ary arteries(3) significant stenosis of two major coronary arteries,

including high grade stenosis of the proximal leftanterior descending coronary artery

Significant stenosis was defined for these studies as �70%of major coronary arteries or �50% of the LM stem. The pre-sence of impaired LV function increases the absolute prog-nostic advantage of surgery over medical treatment in allcategories. This information comes from two major random-ized studies: the European Coronary Artery study and theNorth American CASS study.287,559

Surgery has been convincingly shown to reduce symptomsand ischaemia and to improve quality of life in patients withchronic angina. These effects are evident in a much widerrange of subgroups than in which it has been shown to

improve survival.290 However, despite improvements overtime, operative morbidity and mortality remain importantconsiderations. Thus individual risks and benefits should bediscussed as thoroughly in low-risk patients, in whomsurgery is undertaken on symptomatic grounds alone, as inhigh-risk patients.

The overall operative mortality for CABG is between 1 and4%51,560–563 depending on the population studied, and thereare well-developed risk stratification models available forthe assessment of risk in individual patients.564,565 There isthe paradox that the higher the risk of operation, thegreater is the benefit of surgical over medical treatment.Most patients are angina-free following CABG, but recurrentangina may occur in the years after surgery. Although thelong-term patency rates for the left internal thoracicartery (LITA) graft are extremely good, saphenous veingrafts have a significant rate of attrition. Thrombotic occlu-sion can occur in the early post-operative period, �10% bythe end of the first year, and after 5 years, the vein itselfcan develop atheromatous disease. The patency rate ofvein grafts is 50–60% at 10 years.566,567

Over the last 20 years, the standard procedure has been tograft the LAD with the LITA and use saphenous vein for theother bypass grafts. Because at least 70% of patients arealive 10 years following surgery, the recurrence of symptomsfrom vein graft disease remains a clinical problem. Largeobservational studies have shown that the use of the LITAgraft improves survival and reduces the incidence of thelate MI, recurrent angina, and the need for further cardiacinterventions.568 Recent observational studies havesuggested benefit for bilateral internal thoracic artery(BITA) grafting.569 There appears to be significant survivalbenefit when using BITA grafts irrespective of age, ventricu-lar function, and the presence of diabetes. Furthermore,the benefit of using BITA increased with the duration offollow-up, particularly in terms of the need for redosurgery, which at 10 years was 40% for single ITA and 8%for BITA grafting in well-matched patients. Ten years afterCABG 90% of ITA grafts continue to function well.With experience, including the use of skeletonized ITApedicles, the risk of sternal devascularization and sub-sequent dehiscence is much reduced, even in diabetics.Other arterial grafts which have been used include theradial artery and the right gastroepiploic artery. The great-est experience has been with the radial artery where reportshave indicated patency rates of .90% in the first 3 years ofsurgery.570,571

The use of extra-corporeal circulation (cardiopulmonarybypass) to perform coronary artery surgery remains themost commonly used approach. But there are risks attached,including a whole-body inflammatory response and the pro-duction of micro-emboli. The need for aortic cannulationand manipulation of the ascending aorta may lead torelease of emboli, especially in elderly, atheromatouspatients. The so-called ‘off-pump’ surgery may lead to areduction in peri-operative mortality and morbidity. Therecent introduction of stabilization devices, which allow iso-lation and control of epicardial arteries, facilitates attach-ment of the bypass graft without stopping the heart andhas enabled surgeons to perform surgery without the useof cardiopulmonary bypass. Randomized trials comparingoff-pump with the standard procedure are now available.Although the use of blood products was reduced in the

38 ESC Guidelines

off-pump group (3 vs. 13%) and the release of CK-MB isoen-zynme was 41% less in the off-pump group, there were nodifferences in the peri-operative complication rates. Therewas no difference in outcome in the first 1–3 years aftersurgery between off-pump and standard groups.572,573

More recently, Khan et al.,574 in a further randomized trialwith angiographic follow-up of 3–6 months, showed a signifi-cant reduction in graft patency (90 vs. 98%) in the off-pumpgroup. These studies suggest that the use of off-pumpsurgery is not a panacea but should be applied cautiouslyand selectively to patients with good target vessels andsignificant co-morbidity.

Percutaneous coronary interventionAlthough percutaneous transluminal angioplasty was initiallyonly used for the treatment of one-vessel disease, advancesin experience, equipment, particularly stents, and adjuvanttherapy, have lead to a considerably expanded role for thismodality of treatment in recent years. In patients withstable angina and suitable coronary anatomy, the use ofstents and adequate adjuvant therapy allows a competentpractitioner to perform either one- or multi-vessel PCIwith a high likelihood of initial procedural success andacceptable risk.575 The risk of death associated with the pro-cedure in routine angioplasty is �0.3–1%, although this canvary quite considerably. Contrary to the case of bypasssurgery, on available evidence, PCI compared with medicaltherapy does not seem to provide substantial survivalbenefit in stable angina.576

Trial-based evidence indicates, however, that PCI is moreoften effective than medical treatment in reducing eventsthat impair quality of life (angina pectoris, dyspnoea, andthe need for re-hospitalisation or limitation of exercisecapacity). The ACME investigators577 demonstrated superiorcontrol of symptoms and better exercise capacity in patientsmanaged with PCI when compared with medical therapy.Death and MI were similar in both groups. However,mid-term results in patients with two-vessel disease didnot demonstrate superior control of symptoms comparedwith medical therapy (similar improvement in exercise dur-ation, freedom from angina, and improvement in quality oflife at the time of 6-month follow-up) as was experienced bypatients with one-vessel disease.578 This small study(n ¼ 328) suggests that PCI may be less effective in control-ling symptoms in patients with two-vessel and stable anginawhen compared with one-vessel disease.The RITA-2 trial579 showed that PCI results in better control

of symptoms of ischaemia and improves exercise capacitycompared with medical therapy, but is associated with ahigher combined endpoint of death and peri-procedural MI.In this trial, 1018 patients (62% with multi-vessel CAD and34% with significant disease in the proximal segment of theleft anterior descending coronary artery) with stable anginawere randomized to PCI or medical therapy and followedfor a mean of 2.7 years. Patients who had inadequatecontrol of their symptoms with optimal medical therapywere allowed to cross-over to myocardial revascularization.Death and definite MI occurred in 6.3% of the PCI patientsand 3.3% of the medical patients (P ¼ 0.02). Of the 18deaths (11 PCI and seven medical), only eight were due toheart disease. Twenty-three per cent of the medical patientsrequired a revascularization procedure during follow-up.Angina improved in both groups, but there was a 16.5%

absolute excess of worse angina in the medical group at 3months following randomization (P, 0.001). Duringfollow-up, 7.9% of the patients randomized to PCI requiredCABG surgery when compared with 5.8% of the medicalpatients. AVERT580 randomly assigned 341 patients withstable CAD, normal LV function, and Class I and/or II anginato PCI or medical therapy with 80 mg daily atorvastatin. At18 months follow-up, 13% of the medically treated grouphad ischaemic events when compared with 21% of the PCIgroup (P ¼ 0.048). Angina relief was greater in thosetreated with PCI. These data suggest that in low-risk patientswith stable CAD, medical treatment including aggressivelipid-lowering therapy may be as effective as PCI in reducingischaemic events. Greater improvement in anginal symptomsoccurred with PCI.

Elective stent insertion and drug-eluting stents (DES). In ameta analysis of 29 trials involving 9918 patients, therewas no evidence for a difference between routine coronarystenting and standard balloon angioplasty in terms of deathor MI or the need for CABG surgery. However, coronary stent-ing reduces the rate of restenosis and the need for repeatPCI,581 findings confirmed in a further more recentmeta-analysis.582 However in-stent restenosis remains alimitation in the efficacy of PCI for patients with stablecoronary disease, with a need for target lesion revasculari-zation between 5 and 25%.Drug-eluting stents have been the focus of attention of

interventional coronary therapy after the RAVEL study.583

The frequently interchangeable use of the term ‘coatedstent’ and ‘drug-eluting stent’ is misleading becausecoated stent also includes the so-called passive coatings,which have failed to prove their benefit and, in someseries, have even showed harmful effect. Hence, the termdrug-eluting stent is recommended instead of coatedstent. Presently, three drugs have shown significantly posi-tive effects in prospective randomized studies (paclitaxel,sirolimus, and its derivative everolimus). To date, random-ized trials include only patients with one-vessel diseaseand with stable or unstable angina. The use of drug-eluting stents shows a consistently better treatment effectcompared to bare metal stents, reducing the risk of resteno-sis and major adverse cardiac events including target vesselrevascularization. Reported incidence of major adversecardiac events over 9 months range between 7.1 and10.3% with drug-eluting stents compared with between13.3 and 18.9.584–586 More specific guidelines on the use ofDES are available in the ESC guidelines on PCI.587

Revascularization vs. medical therapyAside from studies dealing exclusively with the effects ofeither PCI vs. medical therapy or surgery vs. medicaltherapy, several hybrid studies have investigated theeffects of revascularization, (either PCI or surgery) com-pared with medical therapy. The Asymptomatic CardiacIschaemia Pilot70 study provides additional information com-paring medical therapy with PCI or CABG revascularizationin patients with documented CAD and asymptomatic ischae-mia by both stress testing and ambulatory ECG monitoring.This small study (n ¼ 558) randomized patients withminimal symptoms but evidence of ischaemia on testing,who were suitable for revascularization by PCI or CABG toone of three treatment strategies: angina-guided drug

ESC Guidelines 39

therapy, angina plus ischaemia-guided drug therapy, andrevascularization by PCI or CABG surgery. At 2 years offollow-up, death or MI had occurred in 4.7% of the revascu-larization patients when compared with 8.8% of theischaemia-guided group and 12.1% of the angina-guidedgroup (P, 0.01 for the revascularized group comparedwith ischaemia or angina-guided groups). The results ofthe ACIP trial indicate that higher-risk patients who areasymptomatic or have minimal symptoms but demonstrableischaemia and significant CAD may have a better outcomewith revascularization with either CABG or PCI comparedwith those managed medically.A Swiss study (TIME)588 in elderly patients (mean age 80

years) with severe angina randomized participants toimmediate invasive or continued medical therapy. Of thoserandomized to invasive therapy, 52% received PCI and 21%had CABG. Invasive therapy was associated with a statisti-cally significant improvement in symptoms at 6 months,but the difference was not maintained at 1 year, partlydue to a 48% delayed revascularization rate in the medicallytreated arm. Death and MI were not significantly differentbetween the two treatment strategies. Investigators in theMedicine, Angioplasty or Surgery Study (MASS)589 random-ized patients with stable angina and isolated disease ofthe left descending coronary artery to medical treatmentor PCI (including stenting) or CABG using a combined end-point of cardiac death, MI, and refractory angina requiringrepeat revascularization by surgery. At 3 years of follow-up,this combined endpoint occurred in 24% of PCI patients, in17% of medical patients, and in 3% of surgical patients.Importantly, there was no significant difference in overallsurvival in the three groups. Death or MI occurred in 1% ofthe CABG group, 2% of the PCI group, and 1.4% of themedically treated group.

PCI vs. surgeryA large number of clinical trials have compared PCI withsurgery in order to establish the choice of revascularizationtechnique, both before and subsequent to the introductionof stenting,562,597,598 and in multi-vessel as well as one-vessel disease. Meta-analysis of trials conducted before1995,599 when coronary stenting was rare, revealed no sig-nificant differences in the treatment strategies for eitherdeath and the combined endpoint of death and MI.Mortality during the initial hospitalization for the procedureoccurred in 1.3% of the CABG group and 1% of the PCI group.The need for subsequent revascularization was significantlyhigher in the PCI group, and although patients weresignificantly less likely to have angina 1 year after bypasssurgery than after PCI, by 3 years this difference was nolonger statistically significant. Results from the BARI study,the largest single randomized trial of PCI vs. surgery,not included in this meta-analysis, were nonethelessconsistent with these findings, although a survival advan-tage with bypass surgery was observed in the diabeticsubgroup.590

More recent trials, such as the ARTS600 and SOS trials,597

have incorporated the use of stents as part of PCI. TheARTS 1 trial600 compared the strategy of multiple-stentimplantation with the aim of complete revascularizationvs. bypass surgery in patients with multi-vessel disease.However, this trial was not exclusively among patientswith stable angina; 37 and 35%, respectively, in both arms

had unstable angina, 57 and 60%, respectively, had stableangina, and 6 and 5%, respectively, had silent ischaemia.As in previous analyses of balloon angioplasty, at 1 year,there was no difference between the two groups in termsof rate of death, stroke, or MI. Among patients who survivedwithout stroke or MI, 16.8% of those in the stenting groupunderwent a second revascularization, when comparedwith 3.5% of those in the surgery group. The rate of event-free survival at 1 year was 73.8 percent among the patientswho received stents and 87.8 percent among those whounderwent bypass surgery. As measured 1 year after theprocedure, coronary stenting for multi-vessel disease inselected patients offered a similar outcome in terms ofdeath, stroke, and MI as bypass surgery. However, stentingwas associated with a greater need for repeatedrevascularization.

A meta-analysis including trials of stents560 suggests a mor-tality benefit with CABG compared with PCI at 5 years whichcontinued to 8 years in patients with multi-vessel disease, aswell as significantly less angina and less need for repeatrevascularization. Subgroup analysis of trials with andwithout stents indicated significant heterogeneity betweenthe two groups, with trials performed pre-stents showing atrend towards reduced mortality favouring CABG which wasnot evident in the trials with stents. A more recentmeta-analysis of four randomized controlled trials of per-cutaneous intervention with stents compared with bypasssurgery (n ¼ 3051) showed no significant differencebetween the treatment strategies in the primary endpointof death, MI, or stroke at 1 year.601 However, observationaldata with 3-year follow-up on .60 000 patients from theNew York cardiac registry indicated that for patients withtwo or more diseased coronary arteries, CABG was associatedwith higher adjusted rates of long-term survival thanstenting.602

To summarize, the trial evidence suggests that, outside ofthe population with high-risk indicators which have beenproven to benefit prognostically from surgery, either PCI orsurgery may be considered as an effective option for thetreatment of symptoms. After an initial pharmacologicalapproach, revascularization may be recommended forpatients with suitable anatomy who do not respond ade-quately to medical therapy or for the individual patientwho, regardless of age, wishes to remain physically active(performing regular physical exercise).

In non-diabetic patients with 1–2-vessel disease withouthigh grade stenosis of the proximal LAD in whom angioplastyof one or more lesions has a high likelihood of initial success,PCI is generally the preferred initial approach, influenced byfactors such as the less invasive nature and lower initial riskof the initial procedure and the absence of survivaladvantage of CABG in lower risk subgroups. The individualcircumstances and preferences of each patient mustbe considered carefully when planning the treatmentstrategy.

In asymptomatic patients, revascularization cannotimprove symptoms and the only appropriate indication forrevascularization with PCI would be to reduce the likelihoodof ischaemic complications in the future. Evidence tosupport this strategy is limited only to those patients withobjective evidence of extensive ischaemia, in whom revas-cularization (either PCI or CABG) may reduce the likelihoodof mortality relative to an angina-guided strategy (ACIP).70

40 ESC Guidelines

PCI may be considered for mildly symptomatic patients inthe category of higher-risk ischaemia and severe anatomicCAD only if there is a high likelihood of success and a lowrisk of morbidity or mortality.

Specific patient and lesion subsetsPatients with severely depressed LV function and/or highsurgical risk. Patients in whom surgical risk is prohibitivelyhigh may benefit from revascularization by PCI, particularlywhen residual viability can be demonstrated in the dysfunc-tioning myocardium perfused by the target vessel(s). Thisissue is currently addressed in two large randomizedstudies, the STICH603 and the HEART UK604 trials.

Unprotected LM disease. The LM stem is referred to asunprotected when the distal coronary arteries do notreceive circulation from a bypass graft. Several observa-tional reports605,606 indicate the feasibility of PCI in LMstem disease. More recently, an observational registry hasshown improved results with drug eluting compared withbare metal stents607 holding promise for the use of PCI inLM stem disease in the future. However, surgery shouldremain the preferred approach until the outcome offurther trials are known.

Multi-vessel disease in patients with diabetes. A formal trialcomparing the effect of PCI vs. CABG in diabetics is not yetavailable; however, post hoc subgroup analyses of randomizedtrials comparing these treatment strategies have shownreduced mortality with bypass surgery compared withPCI.608,609 The BARI trial was the largest of these trials andthe only in which a statistical difference in mortality wasdetected between the treatment groups in the diabetics.590,610

Among treated diabetics (n¼ 353), there was an absolutesurvival advantage of 15% for CABG at 5 years (P¼ 0.003).The rate of repeat revascularization was also higher with PCIin diabetics in BARI and was evident too even withstent-assisted PCI (41 vs. 8.4%) in the ARTS study.A limitation of these trials is that they were conducted

before the widespread use of drug-eluting stents or adjuvantperi-procedural antiplatelet therapy. Drug-eluting stentshave reduced the rate of restenosis in diabetic as in non-diabetic patients585,586,611 but the impact of this reductionon mortality in diabetic patients, particularly in multi-vesselPCI, is unknown. Two major trials are underway to addressthis important issue, BARI 2 Diabetes (BARI 2D) andFREEDOM (Future Revascularisation Evaluation in Patientswith Diabetes Mellitus). However, for the present, due con-sideration should be given to the evidence available and PCIshould be used with reservation in diabetics with multi-vessel disease until the results of further trials are known.

Patients with previous bypass graft surgery. There are norandomized controlled trials comparing treatment optionsin patients with previous bypass surgery. Observationaldata suggest that patients with late stenoses of vein graftshave a high mortality rate,612 and re-operation improvedthe outcome of these patients in one observational compari-son.613 Redo surgery may be undertaken on symptomaticgrounds where the anatomy is suitable. However, the oper-ative risk of redo bypass surgery is as high as three-foldgreater than initial surgery,614 and for those with a patentITA graft, there is the additional risk of damage to thisgraft during surgery.

In contrast, PCI can be performed following previous sur-gical revascularization, either in the vein graft or arterialgraft, or the native coronary tree beyond the graft whichis not revascularized, and may provide a useful alternativeto redo surgery for symptomatic relief. Protective filterdevices may be employed to reduce particulate debrisfrom embolizing downstream and causing peri-proceduralmyocardial damage (SAFER)615 when dilating old saphenousvein grafts.

Chronic total occlusions. Chronic total occlusions still rep-resent the most frequent mode of failure of PCI. When theocclusion can be crossed with a guide-wire and the distallumen has been reached, satisfactory results are obtainablewith stent implantation, as shown by several trials,616–618

albeit at the expense of high restenosis rate ranging from32 to 55%. The value of drug-eluting stents in this respectis currently under evaluation. In patients with multi-vesseldisease, failure to treat chronic total occlusions will resultin incomplete revascularization, which could be avoidedwhen the patient is referred for bypass surgery.

Indications for revascularizationIn general, patients who have indications for coronary arter-iography and in whom catheterization reveals severe coron-ary artery stenosis are also potential candidates formyocardial revascularization. In addition, a patient is poten-tially eligible for revascularization if:

(1) medical therapy is unsuccessful in controlling symp-toms to the patient’s satisfaction

(2) non-invasive tests reveal a substantial area of myocar-dium at risk

(3) there is a high likelihood of success and acceptable riskof morbidity and mortality

(4) the patient prefers an interventional rather than amedical approach and is fully informed of the risks ofthis route of therapy in their individual case

An adequate response to therapy must be judged in con-sultation with the patient. For some, Class I symptoms(angina only on strenuous exertion but not during ordinaryactivity) are acceptable, but others may wish for completeabolition of their symptoms. Recommendations for revascu-larization on symptomatic grounds, as summarized in Table 8or below, have taken into account the range of symptomaticgrades for which evidence is available and should be con-strued in this fashion rather than as a directive to performrevascularization across the entire range of symtomatology.What is an acceptable risk of morbidity and mortality shouldalso be considered on an individual basis for each patient.Ideally, patients should not be advised to have a procedurefor which the procedural mortality exceeds their estimatedannual mortality unless there is evidence of substantialprognostic benefit in the longer term or symptoms arehaving a serious impact on their quality of life, despiteappropriate medical therapy.Selection of the method of revascularization should be

based on:

(1) risk of peri-procedural morbidity and morbidity(2) likelihood of success, including factors such as techni-

cal suitability of lesions for angioplasty or surgicalbypass

(3) risk of restenosis or graft occlusion

ESC Guidelines 41

(4) completeness of revascularization. If considering PCIfor multi-vessel disease, is there a high probabilitythat PCI will provide complete revascularization or atleast in the same range as CABG?

(5) diabetic status(6) local hospital experience in cardiac surgery and inter-

ventional cardiology(7) patient’s preference

Contraindications to myocardial revascularization com-prise the following.

(1) Patients with one- or two-vessel CAD without significantproximal LAD stenosis who have mild or no symptomsand have not received an adequate trial of medicaltherapy or have no demonstrable ischaemia or only a

limited area of ischaemia/viability on non-invasivetesting

(2) Borderline (50–70%) coronary stenosis in location otherthan LM and no demonstrable ischaemia on non-invasive testing

(3) Non-significant (,50%) coronary stenosis(4) High risk of procedure-related morbidity or mortality

(.10–15% mortality risk) unless the risk of the pro-cedure is balanced by an expected significant improve-ment in survival or the patient’s quality of life withoutthe procedure is extremely poor

Constant rapid developments in PCI and CABG, as well assignificant progress in medical treatment and secondary pre-vention of stable angina, have generated the need for largerandomizd trials comparing different treatment strategies in

Table 8 Summary of recommendations for revascularization in stable angina

Indication For prognosisa For symptomsb Studies

Class ofrecommendation

Level ofevidence

Class ofrecommendation

Level ofevidence

PCI (assuming suitable anatomy for PCI, appropriate risk stratification, and discussion with the patient)

Angina CCS classes I–IV despite medical therapywith one-vessel disease

I A ACME and MASS

Angina CCS classes I–IV despite medical therapywith multi-vessel disease (non-diabetic)

I A RITA 2 and VA-ACME

Stable angina with minimal (CCS class I) symptomson medication and one-, two-, or three-vesseldisease but objective evidence of large ischaemia

IIb C ACIP

CABG (assuming suitable anatomy for surgery, appropriate risk stratification, and discussion with the patient)

Angina and LM stem disease I A I A CASS, EuropeanCoronary Surgerystudy, VA Study,and Yusefmeta-analysis

Angina and three-vessel disease with objectivelarge ischaemia

I A I A

Angina and three-vessel disease with poorventricular function

I A I A

Angina with two- or three-vessel disease includingsevere disease of the proximal LAD

I A I A

Angina CCS classes I–IV with multi-vesseldisease (diabetic)

IIa B I B BARI, GABI, ERACI-I,SoS, ARTs,Yusef et al.,Hoffman et al.

Angina CCS classes I–IV with multi-vesseldisease (non-diabetic)

I A

Angina CCS classes I–IV despite medical therapyand one-vessel disease including severedisease of the proximal LAD

I B MASS

Angina CCS classes I–IV despite medical therapyand one-vessel disease not including severedisease of the proximal LAD

IIb B

Angina with minimal (CCS class I) symptoms onmedication and one-, two-, or three-vesseldisease but objective evidence of large ischaemia

IIb C ACIP

Recommendations for revascularization on symptomatic grounds take into account the range of symptomatic grades for which evidence is available andshould be construed in this fashion rather than as a directive to perform revascularization across the entire range of symtomatology.CCS, Canadian Cardiovascular Society.aRelates to effects on mortality, cardiac or cardiovascular mortality, or mortality combined with MI.bRelates to changes in angina class, exercise duration, time to angina on treadmill testing, repeat hospitalization for angina, or other parameters of

functional capacity or quality of life.

42 ESC Guidelines

selected groups of patients. Many questions in the manage-ment of stable angina remain incompletely answered, andfurther questions are generated by the development ofnew treatment modalities, necessitating the constant revi-sion and updating of these guidelines and a need for practis-ing clinicians to remain abreast of current literature in thearea in the interim.Recommendations for revascularization to improve

prognosis in patients with stable anginaClass I

(1) CABG for significant LM CAD or its equivalent (i.e.severe stenosis of ostial/proximal segment of left des-cending and circumflex coronary arteries) (level of evi-dence A)

(2) CABG for significant proximal stenosis of three majorvessels, particularly in those patients with abnormalLV function or with early or extensive reversible ischae-mia on functional testing (level of evidence A)

(3) CABG for one- or two-vessel disease with high-gradestenosis of proximal LAD with reversible ischaemia onnon-invasive testing (level of evidence A)

(4) CABG for significant disease with impaired LV functionand viability demonstrated by non-invasive testing(level of evidence B)

Class IIa

(1) CABG for one- or two-vessel CAD without significantproximal LAD stenosis in patients who have survivedsudden cardiac death or sustained ventricular tachy-cardia (level of evidence B)

(2) CABG for significant three-vessel disease in diabeticswith reversible ischaemia on functional testing (levelof evidence C)

(3) PCI or CABG for patients with reversible ischaemia onfunctional testing and evidence of frequent episodesof ischaemia during daily activities (level of evidence C)

Recommendations for revascularization to improvesymptoms in patients with stable anginaClass I

(1) CABG for multi-vessel disease technically suitable forsurgical revascularization in patients with moderate-to-severe symptoms not controlled by medicaltherapy, in whom risks of surgery do not outweighpotential benefits (level of evidence A)

(2) PCI for one-vessel disease technically suitable forpercutaneous revascularization in patients withmoderate-to-severe symptoms not controlled bymedical therapy, in whom procedural risks do not out-weigh potential benefits (level of evidence A)

(3) PCI for multi-vessel disease without high-risk coronaryanatomy, technically suitable for percutaneous revas-cularization in patients with moderate-to-severe symp-toms not controlled by medical therapy, in whomprocedural risks do not outweigh potential benefits(level of evidence A)

Class IIa

(1) PCI for one-vessel disease technically suitable forpercutaneous revascularization in patients with mild-to-moderate symptoms which are nonetheless

unacceptable to the patient, in whom proceduralrisks do not outweigh potential benefits (level of evi-dence A)

(2) CABG for one-vessel disease technically suitable forsurgical revascularization in patients with moderate-to-severe symptoms not controlled by medicaltherapy, in whom operative risk does not outweighpotential benefit (level of evidence A)

(3) CABG for multi-vessel disease technically suitable forsurgical revascularization in patients with mild-to-moderate symptoms which are nonetheless unaccep-table to the patient, in whom operative risk does notoutweigh potential benefit (level of evidence A)

(4) PCI for multi-vessel disease technically suitable forpercutaneous revascularization in patients withmild-to-moderate symptoms which are nonethelessunacceptable to the patient, in whom procedural risksdo not outweigh potential benefits (level of evidence A)

Class IIb

(1) CABG for one-vessel disease technically suitable forsurgical revascularization in patients with mild-to-moderate symptoms which are nonetheless unaccepta-ble to the patient, in whom operative risk is notgreater than the estimated annual mortality (level ofevidence B)

Treatment of stable angina: multi-targeted treatment of amulti-faceted diseaseIn his/her lifetime, the patient with stable angina may meetepisodes of exercise/stress-induced symptomatic myocardialischaemia (angina pectoris), silent ischaemia, progressiveangina, acute coronary syndromes (unstable angina and MI),acute and chronic heart failure, and life-threatening arrhyth-mias. Prolonged periods of stability may alternate withperiods of instability (sudden progression and acute coronarysyndromes). According to the state of the disease, a patientwill require treatment aimed at retardation of the progressionof disease (prevention), management of symptomatic disease(angina pectoris), management of acute coronary syndromes,and management of heart failure or life-threatening arrhyth-mias. The physician should be prepared to offer the appropri-ate therapy at the appropriate time. The different modes ofpreventive therapy, symptomatic medical therapy, such aspercutaneous and surgical coronary revascularization andmanagement of arrhythmias, are all rapidly evolving and soit is recommended that an individual physician operateswithin a team which can offer the appropriate therapy atthe appropriate time with the appropriate skills.

Special subgroups

WomenThe evaluation of chest pain in women is less straightfor-ward than in men at multiple levels, because of genderdifferences in presentation and disease manifestation619

and also the preponderance of male-specific data in thepublished literature.There are numerous differences in the epidemiology and

primary manifestation of CHD in women and men. Stableangina is the most frequent initial manifestation of CHD inwomen, but MI or sudden death the most frequent initialmanifestation in men.40,41,620 Although the incidence of

ESC Guidelines 43

CHD death and MI is greater in men than in women at allages, the incidence of angina in women exceeds that ofmen in post-menopausal age groups. Therefore, it is not sur-prising that at population level, some studies report an evenhigher prevalence of Rose angina questionnaire in middleaged and elderly women than in men of comparableage.31–33,621,622 However, in population-based studies, theincidence of fatal CHD is higher in men with angina thanwomen with angina,620 possibly partly due to misclassifi-cation of angina as CHD in a proportion of women.The diagnosis of angina in women is more difficult than in

men for several reasons. Atypical symptoms are morecommon in women, but this is ‘atypical ’ compared withthe typical symptoms described by men. Patient perceptionof pain and the language used to report symptoms aredifferent between men and women.623

To compound the problem, the correlation betweensymptoms and ‘significant’ luminal obstruction at coronaryangiography is weaker in women than in men. In theCoronary Artery Surgery Study,624 62% of women withtypical angina had significant coronary stenoses, when com-pared with 40% of women with atypical angina and 4% ofwomen with non-ischaemic pain, illustrating the lowerprevalence of angiographically verified CHD in women thanin men for all forms of chest pain, including typical andatypical angina and non-cardiac chest pain.Angina, the symptom complex, may still be associated

with ischaemia even in the absence of obstructive coronarylesions, as in Syndrome X, a phenomenon which is morecommon in women. Microvascular disease and coronaryvasospasm are also more common in women. Ischaemia, inthis context, may be demonstrated electrocardiographi-cally, by perfusion scintigraphy, or other methods and mayrespond appropriately to anti-ischaemic therapy withoutangiographic evidence of epicardial stenosis. Although theabsence of obstructive coronary lesions remains an indicatorof better infarct-free survival than the presence of obstruc-tive disease, there are some emerging data suggesting thatthe prognosis associated with ‘normal’ coronary arteries isnot as benign as once thought.305

When used for the detection of significant coronarydisease, exercise ECG testing has a higher false-positiverate in women (38–67%) than in men (7–44%),140 largelybecause of the lower pretest likelihood of disease,142 but alower false-negative rate in women.625 This results in a highnegative predictive value, signifying that a negative resultof non-invasive testing reliably excludes the presence ofCAD. The difficulties of using exercise testing for diagnosingobstructive CAD in women have led to speculation thatstress imaging may be preferred over standard stresstesting. Myocardial perfusion scintigraphy or echocardio-graphy could be a logical addition to treadmill testing inthis circumstance. However, the sensitivity of radionuclideperfusion scans may be lower in women than men.626

Artefacts due to breast attenuation, usually manifest in theanterior wall, can be an important caveat in the interpret-ation of women’s perfusion scans, especially when 201Tl isused as a tracer. More recently, the use of gated 99mTc sesta-mibi SPECT imaging has been associated with an apparentreduction in breast artefacts.627 Similarly, exercise orpharmacological stress echocardiography may help avoidartefacts specifically due to breast attenuation. Indeed,numerous studies have indicated the value of stress

echocardiography as an independent predictor of cardiacevents in women with known or suspected CAD.171,628,629

Despite its limitations in women, routine exercise ECGtesting has been shown to reduce procedures without loss ofdiagnostic accuracy. Indeed, only 30% of women (in whom areasonably certain diagnosis of CAD could not be reached orexcluded) need to be referred for further testing.630

Although the optimal strategy for diagnosing obstructive CADin women remains to be defined, the Task Force believesthat there are currently insufficient data to justify replacingstandard exercise testing with stress imaging in all womenbeing evaluated for CAD. In many women with a low pretestlikelihood of disease, a negative exercise test resultwill be suf-ficient and imaging procedures will not be required.630

It is important to emphasize that women with objectiveevidence of moderate-to-severe ischaemia at non-invasivetesting should have equal access to coronary arteriographyas men. Furthermore, limited female representation in clini-cal trials of secondary prevention to date is not a justifica-tion to apply guidelines differently to men and womenafter CAD is diagnosed.

It is known that women have a higher morbidity and mor-tality after suffering MI than men, and it has been suggestedby some that less vigorous treatment in women may impacton reduced survival in women after MI.631 A review of 27studies concluded that the reasons for increased early mor-tality among women were older age and the presence ofother unfavourable baseline clinical characteristics.632

Subsequent investigation found an interaction betweengender and age, with a female excess of mortality inyounger patients (,50 years of age) that diminishes withage.633

Reports of the impact of gender on utilization of investi-gations and therapies and on subsequent clinical outcomein stable settings are similarly divergent. In a recent Dutchstudy, 1894 patients (1526 men and 368 women) with angio-graphically documented CAD were evaluated over a 16-yearperiod (1981–97). Over time, the number of angioplasty pro-cedures increased significantly from 11.6–23.2% for men andfrom 17.6–28.0% for women, whereas the number of coron-ary artery bypass procedures decreased in men from 34.9%to 29.5% and from 42.6–30.6% in women.634 However,interpretation of this and other coronary arteriographyregistries is limited by their intrinsic referral bias. Datafrom the Euro Heart Survey of Stable Angina conducted in2003 suggest that significant bias exists against the use,not just of arteriography but also of exercise testing inwomen, even after adjustment for factors such as age,comorbidity, severity of symptoms, and, in the case of arter-iography, results of non-invasive testing.635 In the samestudy, women were less likely to receive revascularizationand were less likely to receive effective secondary preven-tive medical therapy. Such findings suggest that the per-ceived difficulties in diagnosis and limited female-specificliterature regarding the treatment of angina, alongperhaps with more complex social issues, have perpetuatedthe situation where women with stable angina often remainunder-investigated and under-treated.

Diabetes mellitusBoth insulin-dependent diabetes mellitus (type 1) andnon-insulin-dependent diabetes mellitus (type 2) are associ-ated with an increased risk of CVD. Furthermore, CHD

44 ESC Guidelines

mortality is increased three-fold in diabetic men and two- tofive-fold in diabetic women, compared with age- and sex-matched non-diabetic persons.81,636–638 Moreover, anumber of epidemiological reports indicate that in patientswith diabetes, the higher the blood glucose, the greater theincidence of CVD.639,640

The clinical manifestations of CHD in diabetic subjects aresimilar to those in non-diabetic patients, with angina, MI,and heart failure being the most prominent, but the symp-toms tend to occur at an earlier age in diabetic patients.It is generally accepted that the prevalence of asympto-matic ischaemia is increased in patients with diabetes.However, because of considerable variation in inclusionand exclusion criteria as well as screening tests in studiesto date, it is somewhat difficult to estimate the increasedfrequency of silent ischaemia accurately.641

There is growing interest in the use of myocardial perfusionscanning and other techniques to detect ischaemia in asymp-tomatic diabetic individuals642 and firm evidence of the prog-nostic power of perfusion imaging specifically in diabeticpatients.643 There are also data to suggest that individualswith diabetes may have subclinical ventricular dysfunctionwhich negatively impacts on exercise capacity,644 an import-ant endpoint of exercise testing, but the impact of thisfinding on the diagnostic and prognostic information yieldedby conventional testing in a symptomatic population is notclear. Thus, the cardiac assessment of symptomatic ischaemiain diabetic patients should, in general, parallel that in non-diabetic subjects, with similar indications for exercisetesting, myocardial perfusion testing, and coronary arterio-graphy. As CVD accounts for 80% of mortality in patientswith diabetes mellitus,645 emphasis should be placed onearly diagnosis and aggressive treatment in this population.Current strategies for optimal care of patients with dia-

betes mellitus include vigorous and persistent efforts toachieve physiological control of blood glucose and controlof other risk factors such as dyslipidaemia, renal disease,obesity, and smoking. Abundant evidence that long-termmaintenance of near-normal blood glucose levels is protec-tive of patients with diabetes and substantially reducescomplications and mortality in both diabetes type 1 andtype 2 is now available.645–648

Conventional therapies for CHD with nitrates, beta-blockers, calcium-channel blockers, statins, antiplateletsagents, and coronary revascularization procedures havesimilar indications in diabetic and non-diabetic patients.Additionally, ACE-inhibitors are indicated in diabeticpatients with proven vascular disease.253 The relativemerits of PCI and CABG in diabetic patients are discussedin the section on Revascularization. Unfortunately, owingto the chronic metabolic disturbances of diabetes mellitus,these patients usually have a continuous progression ofnative atherosclerotic disease, leading to an extensiveCHD with high rates of multi-vessel disease and of resteno-sis.649,650 Thus, even after successful invasive procedures,good management of CVD risk factors and a tight glycaemiccontrol are essential for good long-term outcome.638

ElderlyAfter the age of 75 years there is an equal prevalence of CADin men and women.651 The disease is more likely to bediffuse and severe; LM coronary artery stenosis and three-vessel disease are more prevalent in older patients, as is

impaired LV function. The evaluation of chest pain syn-dromes in the elderly can be difficult because complaintsof chest discomfort, weakness, and dyspnoea are common,and co-morbid conditions that mimic angina pectoris arefrequently present. Reduced activity levels and bluntedappreciation of ischaemic symptoms become the norm withadvancing age.652 In large community studies of men andwomen .65-years old, those with atypical symptoms andtypical angina were shown to have similar 3 year cardiacmortality rates.20 The performance of exercise testingposes additional problems in the elderly. Functional capacityoften is compromised from muscle weakness and decondi-tioning. More attention must be given to the mechanicalhazards of exercise, and less challenging protocols may bemore appropriate. Arrhythmias occur more frequently withincreasing age, especially at higher workloads.653 Theinterpretation of exercise test results in the elderly differsfrom that in the young. The higher prevalence of diseasemeans that more test results are false negative.654 False-positive test results also are more frequent because of thehigher prevalence of confounders such as prior MI, LV hyper-trophy from valvular diseases, hypertension and conductiondisturbances. Despite these differences, exercise testingremains important also in the elderly. The Task Forcebelieves that exercise ECG testing should remain the initialtest in evaluating elderly patients with suspected of CADunless the patient cannot exercise, in which case it may bereplaced by pharmacological stress imaging.It is important to emphasize that elderly patients with

objective evidence of moderate-to-severe ischaemia at non-invasive testing should have similar access to coronary arter-iography as younger patients. Notably, diagnostic coronaryarteriography has relatively little increased risk (comparedwith younger patients) in older patients undergoing electiveevaluation.243 However, age .75 is an important predictorof contrast-induced nephropathy.655

Medical treatment is more complex in elderly patients.Indeed, changes in drug bioavailability, elimination, andsensitivity mean that dose modification is essential whenprescribing cardiovascular drugs to elderly patients.656

Further issues which should be taken into account whenprescribing for the elderly include risk of drug interactions,polypharmacy, and compliance problems. Nevertheless, inthis patient population, anti-anginal medications are asefficacious in reducing symptoms and statins in improvingprognosis,438 as they are in young patients. Consideringsymptoms as well as prognosis, elderly patients have thesame benefit from medical therapy, angioplasty, andbypass surgery as younger patients.657–659

Chronic refractory anginaDrugs and revascularization procedures, i.e. CABG and per-cutaneous transluminal angioplasty, can adequatelymanage the majority of patients suffering from ischaemicheart disease. However, there are patients who remainseverely disabled by angina pectoris in spite of differentforms of conventional treatment. It is an unfortunate ironythat the prolongation of life due to the improvement ofcardiovascular care and treatment are responsible for anincrease in the number of patients with end-stage ischaemiccoronary disease, some who complain from intractable epi-sodes of angina. The problem of chronic refractory angina

ESC Guidelines 45

was addressed in a Report from the ESC Joint Study Group onthe Treatment of Refractory Angina, published in 2002.660

Chronic stable refractory angina can be defined as a clini-cal diagnosis based on the presence of symptoms of stableangina, thought to be caused by ischaemia due to advancedcoronary disease and which are not controllable by a combi-nation of maximal medical therapy, bypass surgery and per-cutaneous intervention. Non-cardiac causes of chest painshould be excluded, and where appropriate, cognitive beha-vioural therapy, psychological assessment, and/or psychia-tric consultation may be considered.According to the previously mentioned report from the

Joint Study Group, we have no accurate figures on theoccurrence and frequency of refractory angina. A Swedishsurvey of patients referred for coronary arteriographybecause of stable angina pectoris performed in 1994–95showed that nearly 10% of patients were rejected for revas-cularization despite severe symptoms.661,662

The most common reasons that revascularization is notconsidered appropriate are:

(1) Unsuitable anatomy(2) One or several previous bypass grafting and/or PTCA

procedures(3) Lack of available graft conduits(4) Extra-cardiac diseases which increase perioperative

morbidity and mortality(5) Advanced age, often in combination with these factors

Chronic refractory angina requires an effective optimiza-tion of medical treatment assuring the use of differentdrugs in maximal tolerated doses. This issue is extensivelydeveloped in the original document of the Joint StudyGroup. Within the last few years, new modalities exploringnew concepts of therapy are under extensive evaluation,although not all have been successful: neuromodulationtechniques (transcutaneous electric nerve stimulation andspinal cord stimulation), thoracic epidural anaesthesia,endoscopic thoracic sympathectomy, stellate ganglionblockade, transmyocardial or percutaneous laser revascular-ization, angiogenesis, enhanced external counterpulsation,heart transplantation, and drugs that modulate metabolism.Transcutaneous electrical stimulation and spinal cord

stimulation are well-established methods used in severalcentres for the management of refractory angina with posi-tive effects on symptoms and a favourable side-effectprofile.663–665 These techniques have a favourable analgesiceffect even without any improvement in myocardial ischae-mia. A significant increase in the average exercise time ontreadmill testing has however been observed. The numberof published reports and the number of patients enrolledin clinical trials are small, and the long-term effects ofthese techniques are unknown.Enhanced external counterpulsation (EECP) is an interest-

ing non-pharmacological technique, which has also beeninvestigated largely in the USA. Two multi-centre registrieshave evaluated the safety and effectiveness of EECP.666–668

The technique is very well tolerated when used over aperiod of 35 hours of active counterpulsation during4–7-week period. Anginal symptoms were improved in�75–80% of patients.Transmyocardial revascularization has been compared

with medical therapy in several studies. In one study (in275 patients with CCS class IV symptoms), 76% of patients

who had undergone transmyocardial revascularizationimproved two or more functional classes after 1 year offollow-up, as compared with 32% (P, 0.001) of the patientswho received medical therapy alone.669 Mortality did notdiffer significantly between the two groups. Other studiesof transmyocardial revascularization (either surgically or per-cutaneously) have been unable to confirm this benefit.670,671

In particular, a recent randomized controlled trial of 298patients showed that treatment with percutaneous myocar-dial laser provides no benefit beyond that of a similar shamprocedure in patients blinded to their treatment.672

Furthermore, measurement of regional myocardial bloodflow and coronary flow reserve by means of PET has failedto show imporved perfusion following this procedure.673

International studies and registries are urgently requiredto clarify the epidemiology of this condition and furtherresearch is encouraged to definitely establish the roles ofexisting and novel alternative techniques to manage thesepatients.

Conclusions and Recommendations

(1) Angina pectoris due to coronary atherosclerosis is acommon and disabling disorder. Although compatiblewith longevity, there is an increased risk of progressionto MI and/or death. With proper management, thesymptoms can usually be controlled and the prognosissubstantially improved.

(2) Every patient with suspected stable angina requiresprompt and appropriate cardiological investigation toensure that the diagnosis is correct and that the prog-nosis is evaluated. As a minimum, each patient shouldhave a carefully taken history and physical examin-ation, a comprehensive risk factor evaluation, and aresting ECG.

(3) To confirm the diagnosis and plan further management,an initial non-invasive strategy, using exercise ECG,stress echo, or myocardial perfusion scintigraphy ismost appropriate. This allows an assessment of thelikelihood of and the severity of CHD in patients withmild-to-moderate symptoms and effective risk stratifi-cation. In many patients, coronary arteriography mayfollow, but an initial invasive strategy without priorfunctional testing is rarely indicated, and may onlybe considered for patients with new onset severe oruncontrolled symptoms.

(4) The exercise ECG should be interpreted with attentionto haemodynamic response, workload achieved, andclinical features of the individual as well as symptomsand ST-segment response. Alternative investigationsare needed when exercise is not possible or the ECG isnot interpretable, or in addition to exercise testingwhen the diagnosis remains uncertain or functionalassessment is inadequate.

(5) In addition to their role in intial assessment of stableangina symptoms, myocardial perfusion scintigraphyand stress echocardiography are of particular value indemonstrating the extent and localization of myocar-dial ischaemia.

(6) Echocardiography and other non-invasive imaging mod-alities, such as magnetic resonance, are helpful in eval-uating ventricular function.

46 ESC Guidelines

(7) The interpretation of chest pain is particularly difficultin young and middle-aged women. The classicalsymptom complex of chronic stable angina, which is areliable indicator of obstructive coronary disease inmen, is not so in younger women. This problem is com-pounded by the higher prevalence of coronary arteryspasm and ‘Syndrome X’ in women with chest painand by the frequency of ‘false-positive’ exercisetests. However, these complexities should not preventappropriate investigation and treatment of women,particularly the use of non-invasive investigations forthe purposes of risk stratification and use of secondarypreventative therapies.

(8) After initial risk evaluation, risk-factor correction bylife-style modification should be implemented inaddition to pharmacological intervention as necessary.Strict diabetic control and weight control alongwith smoking cessation strategies are strongly advisedin all patients with coronary disease, and bloodpressure control is extremely important. Successfulrisk-factor management may modify the initial riskassessment.

(9) In terms of specific pharmacological therapy, short-acting nitrates, when tolerated, may be used toprovide acute symtomatic relief. In the absence of con-traindications or intolerance, patients with stableangina pectoris should be treated with aspirin(75 mg/day) and statin therapy. A beta-blocker shouldbe used first line or, alternatively, a calcium-channelblocker or long-acting nitrate may be used to provideanti-anginal effects, as described earlier, withadditional therapy as necessary. ACE-inhibition is indi-cated in patients with co-existing ventricular dysfunc-tion, hypertension, or diabetes and should be stronglyconsidered in patients with other high-risk features.Beta-blockers should be recommended in all post-MIpatients and in patients with LV dysfunction, unlesscontraindicated.

(10) Anti-anginal drug treatment should be tailored to theneeds of the individual patient and should be moni-tored individually. The dosing of one drug should beoptimized before adding another one, and it is advise-able to switch drug combinations before attempting athree drug regimen.

(11) If not undertaken for further prognostic evaluation,coronary arteriography should be undertaken whensymptoms are not satisfactorily controlled by medicalmeans, with a view to revascularization.

(12) PCI is an effective treatment for stable angina pectorisand is indicated for patients with angina not satisfac-torily controlled by medical treatment when thereare anatomically suitable lesions. Restenosis continuesto be a problem, which has been diminished byadvances in stenting technology. There is no evidencethat PCI reduces the risk of death in patients withstable angina compared with medical or surgicaltherapy.

(13) CABG is highly effective in relieving the symptoms ofstable angina and reduces the risk of death over long-term follow-up in particular subgroups of patients,such as those with LM stem stenosis, proximal LADstenosis, and three-vessel disease, especially if LVfunction is impaired.

(14) There is evidence674,675 that some gaps remainbetween best practice and usual care in the manage-ment of stable angina. Specifically, many individualswith stable angina are not referred for functionaltesting to confirm the diagnosis and determine progno-sis. Furthermore, there is worrying variability in ratesof prescription of statins and aspirin. Because of thewide variations in the quality of care afforded to suf-ferers from angina, there is a strong case for auditingseveral components of the management of the con-dition. As is the practice in some countries, local,regional, or national registers of the outcome of PCIand surgery should be created and maintained.

References

1. De Backer G, Ambrosioni E, Borch-Johnsen K, Brotons C, Cifkova R,Dallongeville J et al. European guidelines on cardiovascular diseaseprevention in clinical practice: third joint task force of European andother societies on cardiovascular disease prevention in clinical practice(constituted by representatives of eight societies and by invitedexperts). Eur J Cardiovasc Prev Rehabil 2003;10:S1–S10.

2. Heberden. Some account of a disorder of the breast. Med Transact R CollPhys Lond 1772;2:59.

3. Parry CH. An inquiry into the symptoms and causes of syncope anginosa,commonly called angina pectoris. Edinburgh, London: Bryce, Murray andCallow;1799.

4. Crea F, Gaspardone A. New look to an old symptom: angina pectoris.Circulation 1997;96:3766–3773.

5. Tomai F, Crea F, Chiariello L, Gioffre PA. Ischemic preconditioning inhumans: models, mediators, and clinical relevance. Circulation1999;100:559–563.

6. Cohn PF, Fox KM, Daly C. Silent myocardial ischemia. Circulation2003;108:1263–1277.

7. Gould KL, Kirkeeide RL, Buchi M. Coronary flow reserve as a physiologicmeasure of stenosis severity. J Am Coll Cardiol 1990;15:459–474.

8. Gould KL. Effects of coronary stenoses on coronary flow reserve andresistance. Am J Cardiol 1974;34:48–55.

9. Mohlenkamp S, Hort W, Ge J, Erbel R. Update on myocardial bridging.Circulation 2002;106:2616–2622.

10. Pupita G, Maseri A, Kaski JC, Galassi AR, Gavrielides S, Davies G et al.Myocardial ischemia caused by distal coronary-artery constriction instable angina pectoris. N Engl J Med 1990;323:514–520.

11. Braunwald E. Unstable angina. A classification. Circulation 1989;80:410–414.

12. Myocardial infarction redefined–a consensus document of The JointEuropean Society of Cardiology/American College of CardiologyCommittee for the redefinition of myocardial infarction. Eur Heart J2000;21:1502–1513.

13. Yamagishi M, Terashima M, Awano K, Kijima M, Nakatani S, Daikoku Set al. Morphology of vulnerable coronary plaque: insights from follow-upof patients examined by intravascular ultrasound before an acute coron-ary syndrome. J Am Coll Cardiol 2000;35:106–111.

14. Libby P. Molecular bases of the acute coronary syndromes. Circulation1995;91:2844–2850.

15. Buffon A, Biasucci LM, Liuzzo G, D’Onofrio G, Crea F, Maseri A.Widespread coronary inflammation in unstable angina. N Engl J Med2002;347:5–12.

16. Rose GA, Blackburn H. Cardiovascular survey methods. Monogr SerWorld Health Organ 1968;56:1–188.

17. Cook DG, Shaper AG, MacFarlane PW. Using the WHO (Rose) angina ques-tionnaire in cardiovascular epidemiology. Int J Epidemiol 1989;18:607–613.

18. LampeFC,WhincupPH,Wannamethee SG, Ebrahim S,Walker M, Shaper AG.Chest pain on questionnaire and prediction ofmajor ischaemic heart diseaseevents in men. Eur Heart J 1998;19:63–73.

19. Bulpitt CJ, Shipley MJ, Demirovic J, Ebi-Kryston KL, Markowe HL, Rose G.Predicting death from coronary heart disease using a questionnaire. Int JEpidemiol 1990;19:899–904.

20. LaCroix AZ, Guralnik JM, Curb JD, Wallace RB, Ostfeld AM, HennekensCH. Chest pain and coronary heart disease mortality among older menand women in three communities. Circulation 1990;81:437–446.

ESC Guidelines 47

21. Friedman LM, Byington RP. Assessment of angina pectoris after myocar-dial infarction: comparison of ‘Rose Questionnaire’ with physician judg-ment in the Beta-Blocker Heart Attack Trial. Am J Epidemiol1985;121:555–562.

22. Wilcosky T, Harris R, Weissfeld L. The prevalence and correlates of RoseQuestionnaire angina among women and men in the Lipid ResearchClinics Program Prevalence Study population. Am J Epidemiol1987;125:400–409.

23. Garber CE, Carleton RA, Heller GV. Comparison of ‘Rose QuestionnaireAngina’ to exercise thallium scintigraphy: different findings in malesand females. J Clin Epidemiol 1992;45:715–720.

24. Erikssen J, Forfang K, Storstein O. Angina pectoris in presumably healthymiddle-aged men. Validation of two questionnaire methods in makingthe diagnosis of angina pectoris. Eur J Cardiol 1977;6:285–298.

25. Nicholson A, White IR, Macfarlane P, Brunner E, Marmot M. Rose ques-tionnaire angina in younger men and women: gender differences inthe relationship to cardiovascular risk factors and other reportedsymptoms. J Clin Epidemiol 1999;52:337–346.

26. Rose G, Hamilton PS, Keen H, Reid DD, McCartney P, Jarrett RJ.Myocardial ischaemia, risk factors and death from coronary heart-disease. Lancet 1977;1:105–109.

27. Hagman M, Jonsson D, Wilhelmsen L. Prevalence of angina pectoris andmyocardial infarction in a general population sample of Swedish men.Acta Med Scand 1977;201:571–577.

28. Shaper AG, Pocock SJ, Walker M, Cohen NM, Wale CJ, Thomson AG.British Regional Heart Study: cardiovascular risk factors in middle-agedmen in 24 towns. Br Med J (Clin Res Ed) 1981;283:179–186.

29. Bainton D, Baker IA, Sweetnam PM, Yarnell JW, Elwood PC. Prevalenceof ischaemic heart disease: the Caerphilly and Speedwell surveys.Br Heart J 1988;59:201–206.

30. Krogh V, Trevisan M, Panico S, Farinaro E, Mancini M, Menotti A et al.Prevalence and correlates of angina pectoris in the Italian nine commu-nities study. Research Group ATS-RF2 of the Italian National ResearchCouncil. Epidemiology 1991;2:26–32.

31. Ford ES, Giles WH, Croft JB. Prevalence of nonfatal coronary heartdisease among American adults. Am Heart J 2000;139:371–377.

32. Smith WC, Kenicer MB, Tunstall-Pedoe H, Clark EC, Crombie IK.Prevalence of coronary heart disease in Scotland: Scottish HeartHealth Study. Br Heart J 1990;64:295–298.

33. Mittelmark MB, Psaty BM, Rautaharju PM, Fried LP, Borhani NO, Tracy RPet al. Prevalence of cardiovascular diseases among older adults. TheCardiovascular Health Study. Am J Epidemiol 1993;137:311–317.

34. Keys A. Wine, garlic, and CHD in seven countries. Lancet 1980;1:145–146.

35. Lampe FC, Morris RW, Whincup PH, Walker M, Ebrahim S, Shaper AG. Isthe prevalence of coronary heart disease falling in British men? Heart2001;86:499–505.

36. Fry J. The natural history of angina in a general practice. J R Coll GenPract 1976;26:643–646.

37. Medalie JH, Goldbourt U. Angina pectoris among 10,000 men. II.Psychosocial and other risk factors as evidenced by a multivariate analy-sis of a 5 year incidence study. Am J Med 1976;60:910–921.

38. Yano K, Reed DM, McGee DL. 10 year incidence of coronary heart diseasein the Honolulu Heart Program. Relationship to biologic and lifestylecharacteristics. Am J Epidemiol 1984;119:653–666.

39. Margolis JR, Gillum RF, Feinleib M, Brasch R, Fabsitz R. Community sur-veillance for coronary heart disease: the Framingham CardiovascularDisease survey. Comparisons with the Framingham Heart Study and pre-vious short-term studies. Am J Cardiol 1976;37:61–67.

40. Kannel WB, Feinleib M. Natural history of angina pectoris in theFramingham study. Prognosis and survival. Am J Cardiol1972;29:154–163.

41. Reunanen A, Suhonen O, Aromaa A, Knekt P, Pyorala K. Incidence ofdifferent manifestations of coronary heart disease in middle-agedFinnish men and women. Acta Med Scand 1985;218:19–26.

42. Ducimetiere P, Ruidavets JB, Montaye M, Haas B, Yarnell J. 5 year inci-dence of angina pectoris and other forms of coronary heart disease inhealthy men aged 50–59 in France and Northern Ireland: theProspective Epidemiological Study of Myocardial Infarction (PRIME)Study. Int J Epidemiol 2001;30:1057–1062.

43. Sigurdsson E, Thorgeirsson G, Sigvaldason H, Sigfusson N. Prevalence ofcoronary heart disease in Icelandic men 1968–1986. The ReykjavikStudy. Eur Heart J 1993;14:584–591.

44. Tunstall-Pedoe H, Kuulasmaa K, Mahonen M, Tolonen H, Ruokokoski E,Amouyel P. Contribution of trends in survival and coronary-event ratesto changes in coronary heart disease mortality: 10-year results from

37 WHO MONICA project populations. Monitoring trends and determi-nants in cardiovascular disease. Lancet 1999;353:1547–1557.

45. Rosengren A, Wilhelmsen L, Hagman M, Wedel H. Natural history of myo-cardial infarction and angina pectoris in a general population sample ofmiddle-aged men: a 16-year follow-up of the Primary Prevention Study,Goteborg, Sweden. J Intern Med 1998;244:495–505.

46. Murabito JM, Evans JC, Larson MG, Levy D. Prognosis after the onset ofcoronary heart disease. An investigation of differences in outcomebetween the sexes according to initial coronary disease presentation.Circulation 1993;88:2548–2555.

47. Juul-Moller S, Edvardsson N, Jahnmatz B, Rosen A, Sorensen S, OmblusR. Double-blind trial of aspirin in primary prevention of myocardialinfarction in patients with stable chronic angina pectoris. The SwedishAngina Pectoris Aspirin Trial (SAPAT) Group. Lancet 1992;340:1421–1425.

48. Dargie HJ, Ford I, Fox KM. Total Ischaemic Burden European Trial(TIBET). Effects of ischaemia and treatment with atenolol, nifedipineSR and their combination on outcome in patients with chronic stableangina. The TIBET Study Group. Eur Heart J 1996;17:104–112.

49. Rehnqvist N, Hjemdahl P, Billing E, Bjorkander I, Eriksson SV, Forslund Let al. Effects of metoprolol vs. verapamil in patients with stable anginapectoris. The Angina Prognosis Study in Stockholm (APSIS). Eur Heart J1996;17:76–81.

50. Pepine CJ, Handberg EM, Cooper-DeHoff RM, Marks RG, Kowey P,Messerli FH et al. A calcium antagonist vs. a non-calcium antagonisthypertension treatment strategy for patients with coronary arterydisease. The International Verapamil-Trandolapril Study (INVEST): a ran-domized controlled trial. JAMA 2003;290:2805–2816.

51. Henderson RA, Pocock SJ, Clayton TC, Knight R, Fox KA, Julian DG et al.7 year outcome in the RITA-2 trial: coronary angioplasty versus medicaltherapy. J Am Coll Cardiol 2003;42:1161–1170.

52. Brunelli C, Cristofani R, L’Abbate A. Long-term survival in medicallytreated patients with ischaemic heart disease and prognostic import-ance of clinical and electrocardiographic data (the Italian CNRMulticentre Prospective Study OD1). Eur Heart J 1989;10:292–303.

53. Benchimol D, Dubroca B, Bernard V, Lavie J, Paviot B, Benchimol H et al.Short- and long-term risk factors for sudden death in patients withstable angina. Int J Cardiol 2000;76:147–156.

54. Stampfer MJ, Krauss RM, Ma J, Blanche PJ, Holl LG, Sacks FM et al.A prospective study of triglyceride level, low-density lipoprotein par-ticle diameter, and risk of myocardial infarction. JAMA 1996;276:882–888.

55. Rosengren A, Dotevall A, Eriksson H, Wilhelmsen L. Optimal risk factorsin the population: prognosis, prevalence, and secular trends; data fromGoteborg population studies. Eur Heart J 2001;22:136–144.

56. Anderson JL, Muhlestein JB, Horne BD, Carlquist JF, Bair TL, Madsen TEet al. Plasma homocysteine predicts mortality independently of tra-ditional risk factors and C-reactive protein in patients with angiographi-cally defined coronary artery disease. Circulation 2000;102:1227–1232.

57. Rosengren A, Hagman M, Wedel H, Wilhelmsen L. Serum cholesterol andlong-term prognosis in middle-aged men with myocardial infarction andangina pectoris. A 16-year follow-up of the Primary Prevention Study inGoteborg, Sweden. Eur Heart J 1997;18:754–761.

58. Pekkanen J, Linn S, Heiss G, Suchindran CM, Leon A, Rifkind BM et al.10 year mortality from cardiovascular disease in relation to cholesterollevel among men with and without preexisting cardiovascular disease.N Engl J Med 1990;322:1700–1707.

59. Tervahauta M, Pekkanen J, Nissinen A. Risk factors of coronary heartdisease and total mortality among elderly men with and without preex-isting coronary heart disease. Finnish cohorts of the Seven CountriesStudy. J Am Coll Cardiol 1995;26:1623–1629.

60. Miettinen H, Lehto S, Salomaa V, Mahonen M, Niemela M, Haffner SMet al. Impact of diabetes on mortality after the first myocardial infarc-tion. The FINMONICA Myocardial Infarction Register Study Group.Diabetes Care 1998;21:69–75.

61. Melchior T, Kober L, Madsen CR, Seibaek M, Jensen GV, Hildebrandt Pet al. Accelerating impact of diabetes mellitus on mortality in theyears following an acute myocardial infarction. TRACE Study Group.Trandolapril Cardiac Evaluation. Eur Heart J 1999;20:973–978.

62. Luscher TF, Creager MA, Beckman JA, Cosentino F. Diabetes and vasculardisease: pathophysiology, clinical consequences, and medical therapy:Part II. Circulation 2003;108:1655–1661.

63. Herlitz J, Karlson BW, Lindqvist J, Sjolin M. Rate and mode of deathduring 5 years of follow-up among patients with acute chest pain withand without a history of diabetes mellitus. Diabet Med 1998;15:308–314.

48 ESC Guidelines

64. Kjaergaard SC, Hansen HH, Fog L, Bulow I, Christensen PD. In-hospitaloutcome for diabetic patients with acute myocardial infarction in thethrombolytic era. Scand Cardiovasc J 1999;33:166–170.

65. Uusitupa MI, Niskanen LK, Siitonen O, Voutilainen E, Pyorala K. 5-yearincidence of atherosclerotic vascular disease in relation to generalrisk factors, insulin level, and abnormalities in lipoprotein compositionin non-insulin-dependent diabetic and nondiabetic subjects.Circulation 1990;82:27–36.

66. Harris PJ, Harrell FE Jr, Lee KL, Behar VS, Rosati RA. Survival in medi-cally treated coronary artery disease. Circulation 1979;60:1259–1269.

67. Mock MB, Ringqvist I, Fisher LD, Davis KB, Chaitman BR, Kouchoukos NTet al. Survival of medically treated patients in the coronary arterysurgery study (CASS) registry. Circulation 1982;66:562–568.

68. Califf RM, Armstrong PW, Carver JR, D’Agostino RB, Strauss WE. 27thBethesda Conference: matching the intensity of risk factor managementwith the hazard for coronary disease events. Task Force 5. Stratificationof patients into high, medium and low risk subgroups for purposes of riskfactor management. J Am Coll Cardiol 1996;27:1007–1019.

69. Yusuf S, Zucker D, Peduzzi P, Fisher LD, Takaro T, Kennedy JW et al.Effect of coronary artery bypass graft surgery on survival: overview of10-year results from randomised trials by the Coronary Artery BypassGraft Surgery Trialists Collaboration. Lancet 1994;344:563–570.

70. Davies RF, Goldberg AD, Forman S, Pepine CJ, Knatterud GL, Geller Net al. Asymptomatic Cardiac Ischemia Pilot (ACIP) study 2 yearfollow-up: outcomes of patients randomized to initial strategies ofmedical therapy versus revascularization. Circulation 1997;95:2037–2043.

71. Bouchart F, Tabley A, Litzler PY, Haas-Hubscher C, Bessou JP, Soyer R.Myocardial revascularization in patients with severe ischaemic leftventricular dysfunction. Long term follow-up in 141 patients. Eur J Car-diothorac Surg 2001;20:1157–1162.

72. Elefteriades JA, Tolis G Jr, Levi E, Mills LK, Zaret BL. Coronary arterybypass grafting in severe left ventricular dysfunction: excellent survivalwith improved ejection fraction and functional state. J Am Coll Cardiol1993;22:1411–1417.

73. Diamond GA. A clinically relevant classification of chest discomfort.J Am Coll Cardiol 1983;1:574–575.

74. Campeau L. Letter: grading of angina pectoris. Circulation1976;54:522–523.

75. Hlatky MA, Boineau RE, Higginbotham MB, Lee KL, Mark DB, Califf RMet al. A brief self-administered questionnaire to determine functionalcapacity (the Duke Activity Status Index). Am J Cardiol1989;64:651–654.

76. Spertus JA, Winder JA, Dewhurst TA, Deyo RA, Prodzinski J, McDonell Met al. Development and evaluation of the Seattle Angina Questionnaire:a new functional status measure for coronary artery disease. J Am CollCardiol 1995;25:333–341.

77. Spertus JA, Jones P, McDonell M, Fan V, Fihn SD. Health status predictslong-term outcome in outpatients with coronary disease. Circulation2002;106:43–49.

78. Malik S, Wong ND, Franklin SS, Kamath TV, L’Italien GJ, Pio JR et al.Impact of the metabolic syndrome on mortality from coronary heartdisease, cardiovascular disease, and all causes in United States adults.Circulation 2004;110:1245–1250.

79. Girman CJ, Rhodes T, Mercuri M, Pyorala K, Kjekshus J, Pedersen TRet al. The metabolic syndrome and risk of major coronary events inthe Scandinavian Simvastatin Survival Study (4S) and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).Am J Cardiol 2004;93:136–141.

80. Horne BD, Anderson JL, John JM, Weaver A, Bair TL, Jensen KR et al.Which white blood cell subtypes predict increased cardiovascular risk?J Am Coll Cardiol 2005;45:1638–1643.

81. Haffner SM. Coronary heart disease in patients with diabetes. N Engl JMed 2000;342:1040–1042.

82. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality fromcoronary heart disease in subjects with type 2 diabetes and in nondia-betic subjects with and without prior myocardial infarction. N Engl JMed 1998;339:229–234.

83. Gerstein HC, Pais P, Pogue J, Yusuf S. Relationship of glucose and insulinlevels to the risk of myocardial infarction: a case-control study. J AmColl Cardiol 1999;33:612–619.

84. Hu FB, Stampfer MJ, Solomon CG, Liu S, Willett WC, Speizer FE et al.The impact of diabetes mellitus on mortality from all causes and coron-ary heart disease in women: 20 years of follow-up. Arch Intern Med2001;161:1717–1723.

85. Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for car-diovascular disease independent of high-density lipoprotein cholesterollevel: a meta-analysis of population-based prospective studies.J Cardiovasc Risk 1996;3:213–219.

86. Culleton BF, Larson MG, Evans JC, Wilson PW, Barrett BJ, Parfrey PSet al. Prevalence and correlates of elevated serum creatinine levels:the Framingham Heart Study. Arch Intern Med 1999;159:1785–1790.

87. Stamler J, Dyer AR, Shekelle RB, Neaton J, Stamler R. Relationship ofbaseline major risk factors to coronary and all-cause mortality, and tolongevity: findings from long-term follow-up of Chicago cohorts.Cardiology 1993;82:191–222.

88. Neaton JD, Blackburn H, Jacobs D, Kuller L, Lee DJ, Sherwin R et al.Serum cholesterol level and mortality findings for men screened in theMultiple Risk Factor Intervention Trial. Multiple Risk Factor InterventionTrial Research Group. Arch Intern Med 1992;152:1490–1500.

89. Goldbourt U, Holtzman E, Neufeld HN. Total and high density lipoproteincholesterol in the serum and risk of mortality: evidence of a thresholdeffect. Br Med J (Clin Res Ed) 1985;290:1239–1243.

90. Castelli WP, Garrison RJ, Wilson PW, Abbott RD, Kalousdian S, Kannel WB.Incidence of coronary heart disease and lipoprotein cholesterol levels.The Framingham Study. JAMA 1986;256:2835–2838.

91. Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, Castelli WP, Knoke JDet al. High-density lipoprotein cholesterol and cardiovascular disease.Four prospective American studies. Circulation 1989;79:8–15.

92. Shlipak MG, Stehman-Breen C, Vittinghoff E, Lin F, Varosy PD, Wenger NKet al. Creatinine levels and cardiovascular events in women with heartdisease: do small changes matter? Am J Kidney Dis 2004;43:37–44.

93. Fried LF, Shlipak MG, Crump C, Bleyer AJ, Gottdiener JS, Kronmal RAet al. Renal insufficiency as a predictor of cardiovascular outcomes andmortality in elderly individuals. J Am Coll Cardiol 2003;41:1364–1372.

94. Cockroft DW, Gault MH. Prediction of creatinine clearance from serumcreatinine. Nephron 1976;16:31–42.

95. Arcavi L, Behar S, Caspi A, Reshef N, Boyko V, Knobler H. High fastingglucose levels as a predictor of worse clinical outcome in patientswith coronary artery disease: results from the Bezafibrate InfarctionPrevention (BIP) study. Am Heart J 2004;147:239–245.

96. Muhlestein JB, Anderson JL, Horne BD, Lavasani F, Allen Maycock CA,Bair TL et al. Effect of fasting glucose levels on mortality rate inpatients with and without diabetes mellitus and coronary arterydisease undergoing percutaneous coronary intervention. Am Heart J2003;146:351–358.

97. Fisman EZ, Motro M, Tenenbaum A, Boyko V, Mandelzweig L, Behar S.Impaired fasting glucose concentrations in nondiabetic patients withischaemic heart disease: a marker for a worse prognosis. Am Heart J2001;141:485–490.

98. Korpilahti K, Syvanne M, Engblom E, Hamalainen H, Puukka P, Ronnemaa T.Components of the insulin resistance syndrome are associated with pro-gression of atherosclerosis in non-grafted arteries 5 years after coronaryartery bypass surgery. Eur Heart J 1998;19:711–719.

99. Wilson PW, Cupples LA, Kannel WB. Is hyperglycemia associated withcardiovascular disease? The Framingham Study. Am Heart J 1991;121:586–590.

100. Smith NL, Barzilay JI, Shaffer D, Savage PJ, Heckbert SR, Kuller LH et al.Fasting and 2-hour postchallenge serum glucose measures and risk ofincident cardiovascular events in the elderly: the CardiovascularHealth Study. Arch Intern Med 2002;162:209–216.

101. Park S, Barrett-Connor E, Wingard DL, Shan J, Edelstein S. GHb is abetter predictor of cardiovascular disease than fasting or postchallengeplasma glucose in women without diabetes. The Rancho Bernardo Study.Diabetes Care 1996;19:450–456.

102. Khaw KT, Wareham N, Luben R, Bingham S, Oakes S, Welch A et al.Glycated haemoglobin, diabetes, and mortality in men in Norfolkcohort of european prospective investigation of cancer and nutrition(EPIC-Norfolk). BMJ 2001;322:15–18.

103. Kip KE, Marroquin OC, Kelley DE, Johnson BD, Kelsey SF, Shaw LJ et al.Clinical importance of obesity versus the metabolic syndrome in cardi-ovascular risk in women: a report from the Women’s IschemiaSyndrome Evaluation (WISE) study. Circulation 2004;109:706–713.

104. Guclu F, Ozmen B, Hekimsoy Z, Kirmaz C. Effects of a statin group drug,pravastatin, on the insulin resistance in patients with metabolicsyndrome. Biomed Pharmacother 2004;58:614–618.

105. Held C, Hjemdahl P, Rehnqvist N, Wallen NH, Bjorkander I, Eriksson SVet al. Fibrinolytic variables and cardiovascular prognosis in patientswith stable angina pectoris treated with verapamil or metoprolol.Results from the Angina Prognosis study in Stockholm. Circulation1997;95:2380–2386.

ESC Guidelines 49

106. Held C, Hjemdahl P, Rehnqvist N, Bjorkander I, Forslund L, Brodin Uet al. Cardiovascular prognosis in relation to apolipoproteins andother lipid parameters in patients with stable angina pectoris treatedwith verapamil or metoprolol: results from the Angina Prognosis Studyin Stockholm (APSIS). Atherosclerosis 1997;135:109–118.

107. Nygard O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE.Plasma homocysteine levels and mortality in patients with coronaryartery disease. N Engl J Med 1997;337:230–236.

108. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitativeassessment of plasma homocysteine as a risk factor for vasculardisease. Probable benefits of increasing folic acid intakes. JAMA1995;274:1049–1057.

109. Haverkate F, Thompson SG, Pyke SD, Gallimore JR, Pepys MB. Productionof C-reactive protein and risk of coronary events in stable and unstableangina. European Concerted Action on Thrombosis and DisabilitiesAngina Pectoris Study Group. Lancet 1997;349:462–466.

110. Thompson SG, Kienast J, Pyke SD, Haverkate F, van de Loo JC.Hemostatic factors and the risk of myocardial infarction or suddendeath in patients with angina pectoris. European Concerted Action onThrombosis and Disabilities Angina Pectoris Study Group. N Engl J Med1995;332:635–641.

111. Jansson JH, Olofsson BO, Nilsson TK. Predictive value of tissue plasmino-gen activator mass concentration on long-term mortality in patientswith coronary artery disease. A 7-year follow-up. Circulation1993;88:2030–2034.

112. Held C, Hjemdahl P, Rehnqvist N, Wallen NH, Forslund L, Bjorkander I et al.Haemostatic markers, inflammatory parameters and lipids in male andfemale patients in the Angina Prognosis Study in Stockholm (APSIS). A com-parison with healthy controls. J Intern Med 1997;241:59–69.

113. Blake GJ, Ridker PM. Inflammatory bio-markers and cardiovascular riskprediction. J Intern Med 2002;252:283–294.

114. Zebrack JS, Muhlestein JB, Horne BD, Anderson JL. C-reactive protein andangiographic coronary artery disease: independent and additive predictorsof risk in subjects with angina. J Am Coll Cardiol 2002;39:632–637.

115. Pearson TA. New tools for coronary risk assessment: what are theiradvantages and limitations? Circulation 2002;105:886–892.

116. Bogaty P BJ, Boyer L, Simard S, Joseph L, Bertrand F, Dagenais GR.Fluctuating inflammatory markers in patients with stable ischaemicheart disease. Arch Intern Med 2005;165:221–226.

117. Kragelund C GB, Kober L, Hildebrandt P, Steffensen R. N-terminalpro-B-type natriuretic peptide and long-term mortality in stable coro-nary heart disease. N Engl J Med 2005;352:666–675.

118. Andreotti F, Becker FC. Atherothrombotic disorders: new insights fromhematology. Circulation 2005;111:1855–1863.

119. Norhammar A, Malmberg K, Diderholm E, Lagerqvist B, Lindahl B, Ryden Let al. Diabetes mellitus: the major risk factor in unstable coronary arterydisease even after consideration of the extent of coronary artery diseaseand benefits of revascularization. J Am Coll Cardiol 2004;43:585–591.

120. Bartnik M, Ryden L, Ferrari R, Malmberg K, Pyorala K, Simoons M et al.The prevalence of abnormal glucose regulation in patients with coro-nary artery disease across Europe. The Euro Heart Survey on diabetesand the heart. Eur Heart J 2004;25:1880–1890.

121. Dash H, Lipton MJ, Chatterjee K, Parmley WW. Estimation of pulmonaryartery wedge pressure from chest radiograph in patients with chroniccongestive cardiomyopathy and ischaemic cardiomyopathy. Br Heart J1980;44:322–329.

122. Chakko S, Woska D, Martinez H, de Marchena E, Futterman L, Kessler KMet al. Clinical, radiographic, and hemodynamic correlations in chroniccongestive heart failure: conflicting results may lead to inappropriatecare. Am J Med 1991;90:353–359.

123. Weiner DA, Ryan TJ, McCabe CH, Chaitman BR, Sheffield LT, Ferguson JCet al. Prognostic importance of a clinical profile and exercise test inmedically treated patients with coronary artery disease. J Am CollCardiol 1984;3:772–779.

124. Hammermeister KE, DeRouen TA, Dodge HT. Variables predictive of sur-vival in patients with coronary disease. Selection by univariate andmultivariate analyses from the clinical, electrocardiographic, exercise,arteriographic, and quantitative angiographic evaluations. Circulation1979;59:421–430.

125. Witteman JC, Kok FJ, van Saase JL, Valkenburg HA. Aortic calcificationas a predictor of cardiovascular mortality. Lancet 1986;2:1120–1122.

126. Hemingway H, Shipley M, Christie D, Marmot M. Cardiothoracic ratio andrelative heart volume as predictors of coronary heart disease mortality.The Whitehall study 25 year follow-up. Eur Heart J 1998;19:859–869.

127. McCarthy JH, Palmer FJ. Incidence and significance of coronary arterycalcification. Br Heart J 1974;36:499–506.

128. Eggen DA, Strong JP, McGill HC Jr. Coronary calcification. Relationship toclinically significant coronary lesions and race, sex, and topographicdistribution. Circulation 1965;32:948–955.

129. Kjekshus JK, Maroko PR, Sobel BE. Distribution of myocardial injury andits relation to epicardial ST-segment changes after coronary arteryocclusion in the dog. Cardiovasc Res 1972;6:490–499.

130. Kleber AG. ST-segment elevation in the electrocardiogram: a sign ofmyocardial ischemia. Cardiovasc Res 2000;45:111–118.

131. Proudfit WJ, Bruschke AV, MacMillan JP, Williams GW, Sones FM Jr. 15year survival study of patients with obstructive coronary arterydisease. Circulation 1983;68:986–997.

132. Frank CW, Weinblatt E, Shapiro S. Angina pectoris in men. Prognosticsignificance of selected medical factors. Circulation 1973;47:509–517.

133. RubermanW,Weinblatt E, Goldberg JD, Frank CW, Shapiro S, Chaudhary BS.Ventricular premature complexes in prognosis of angina. Circulation1980;61:1172–1182.

134. Lee TH, Boucher CA. Clinical practice. Noninvasive tests in patients withstable coronary artery disease. N Engl J Med 2001;344:1840–1845.

135. ESC Working Group on Exercise Physiology, Physiopathology andElectrocardiography. Guidelines for cardiac exercise testing. Eur Heart J1993;14:969–988.

136. Gianrossi R, Detrano R, Mulvihill D, Lehmann K, Dubach P, Colombo Aet al. Exercise-induced ST depression in the diagnosis of coronaryartery disease. A meta-analysis. Circulation 1989;80:87–98.

137. Kwok Y, Kim C, Grady D, Segal M, Redberg R. Meta-analysis of exercisetesting to detect coronary artery disease in women. Am J Cardiol1999;83:660–666.

138. Gibson RS. The diagnostic and prognostic value of exercise electrocar-diography in asymptomatic subjects and stable symptomatic patients.Curr Opin Cardiol 1991;6:536–546.

139. Ashley EA, Myers J, Froelicher V. Exercise testing in clinical medicine.Lancet 2000;356:1592–1597.

140. Gibbons RJ, Balady GJ, Bricker JT, Chaitman BR, Fletcher GF, Froelicher VFet al. ACC/AHA 2002 guideline update for exercise testing: summaryarticle. A report of the American College of Cardiology/American HeartAssociation Task Force on Practice Guidelines (Committee to Update the1997 Exercise Testing Guidelines). J Am Coll Cardiol 2002;40:1531–1540.

141. Hung J, Chaitman BR, Lam J, Lesperance J, Dupras G, Fines P et al.Noninvasive diagnostic test choices for the evaluation of coronaryartery disease in women: a multivariate comparison of cardiac fluoro-scopy, exercise electrocardiography and exercise thallium myocardialperfusion scintigraphy. J Am Coll Cardiol 1984;4:8–16.

142. Diamond GA, Forrester JS. Analysis of probability as an aid in the clinicaldiagnosis of coronary-artery disease. N Engl J Med 1979;300:1350–1358.

143. Lauer MS. Exercise electrocardiogram testing and prognosis. Novelmarkers and predictive instruments. Cardiol Clin 2001;19:401–414.

144. Elamin MS, Boyle R, Kardash MM, Smith DR, Stoker JB, Whitaker W et al.Accurate detection of coronary heart disease by new exercise test. BrHeart J 1982;48:311–320.

145. Okin PM, Grandits G, Rautaharju PM, Prineas RJ, Cohen JD, Crow RSet al. Prognostic value of heart rate adjustment of exercise-inducedST segment depression in the multiple risk factor intervention trial. JAm Coll Cardiol 1996;27:1437–1443.

146. Froelicher VF, Lehmann KG, Thomas R, Goldman S, Morrison D, Edson Ret al. The electrocardiographic exercise test in a population withreduced workup bias: diagnostic performance, computerized interpret-ation, and multivariable prediction. Veterans Affairs Cooperative Studyin Health Services #016 (QUEXTA) Study Group. Quantitative ExerciseTesting and Angiography. Ann Intern Med 1998;128:965–974.

147. Yamada H, Do D, Morise A, Atwood JE, Froelicher V. Review of studiesusing multivariable analysis of clinical and exercise test data topredict angiographic coronary artery disease. Prog Cardiovasc Dis1997;39:457–481.

148. Stuart RJ Jr, Ellestad MH. National survey of exercise stress testingfacilities. Chest 1980;77:94–97.

149. Jette M, Sidney K, Blumchen G. Metabolic equivalents (METS) in exer-cise testing, exercise prescription, and evaluation of functionalcapacity. Clin Cardiol 1990;13:555–565.

150. Recommendations by the Working Group on Rehabilitation of theEuropean Society of Cardiology. Long-term comprehensive care ofcardiac patients. Eur Heart J 1992;13(Suppl. C):1–45.

151. Borg G, Holmgren A, Lindblad I. Quantitative evaluation of chest pain.Acta Med Scand Suppl 1981;644:43–45.

152. Mark DB, Shaw L, Harrell FE Jr, Hlatky MA, Lee KL, Bengtson JR et al.Prognostic value of a treadmill exercise score in outpatients withsuspected coronary artery disease. N Engl J Med 1991;325:849–853.

50 ESC Guidelines

153. Ciaroni S, Bloch A, Hoffmann JL, Bettoni M, Fournet D. Prognostic valueof dobutamine echocardiography in patients with intermediate coronarylesions at angiography. Echocardiography 2002;19:549–553.

154. Davidavicius G, Kowalski M, Williams RI, D’Hooge J, Di Salvo G,Pierre-Justin G et al. Can regional strain and strain rate measurementbe performed during both dobutamine and exercise echocardiography,and do regional deformation responses differ with different forms ofstress testing? J Am Soc Echocardiogr 2003;16:299–308.

155. Cheitlin MD, Alpert JS, Armstrong WF, Aurigemma GP, Beller GA,Bierman FZ et al. ACC/AHA guidelines for the clinical application ofechocardiography: executive summary. A report of the AmericanCollege of Cardiology/American Heart Association Task Force onpractice guidelines (Committee on Clinical Application ofEchocardiography). Developed in collaboration with the AmericanSociety of Echocardiography. J Am Coll Cardiol 1997;29:862–879.

156. Marwick TH. Current status of stress echocardiography for diagnosis andprognostic assessment of coronary artery disease. Coron Artery Dis1998;9:411–426.

157. Gibbons RJ, Chatterjee K, Daley J, Douglas JS, Fihn SD, Gardin JM et al.ACC/AHA/ACP-ASIM guidelines for the management of patients withchronic stable angina: a report of the American College ofCardiology/American Heart Association Task Force on PracticeGuidelines (Committee on Management of Patients With ChronicStable Angina). J Am Coll Cardiol 1999;33:2092–2197.

158. Schinkel AF, Bax JJ, Geleijnse ML, Boersma E, Elhendy A, Roelandt JRet al. Noninvasive evaluation of ischaemic heart disease: myocardialperfusion imaging or stress echocardiography? Eur Heart J2003;24:789–800.

159. Korosoglou G, Labadze N, Hansen A, Selter C, Giannitsis E, Katus H et al.Usefulness of real-time myocardial perfusion imaging in the evalu-ation of patients with first time chest pain. Am J Cardiol 2004;94:1225–1231.

160. Rocchi G, Fallani F, Bracchetti G, Rapezzi C, Ferlito M, Levorato M et al.Non-invasive detection of coronary artery stenosis: a comparison amongpower-Doppler contrast echo, 99Tc-Sestamibi SPECT and echo wall-motion analysis. Coron Artery Dis 2003;14:239–245.

161. Moir S, Marwick TH. Combination of contrast with stress echocardiogra-phy: a practical guide to methods and interpretation. CardiovascUltrasound 2004;2:15.

162. Cain P, Baglin T, Case C, Spicer D, Short L, Marwick TH. Application oftissue Doppler to interpretation of dobutamine echocardiography andcomparison with quantitative coronary angiography. Am J Cardiol2001;87:525–531.

163. Cain P, Marwick TH, Case C, Baglin T, Dart J, Short L et al. Assessment ofregional long-axis function during dobutamine echocardiography. ClinSci (Lond) 2001;100:423–432.

164. Voigt JU, Exner B, Schmiedehausen K, Huchzermeyer C, Reulbach U,Nixdorff U et al. Strain-rate imaging during dobutamine stress echocar-diography provides objective evidence of inducible ischemia.Circulation 2003;107:2120–2126.

165. Yip G, Abraham T, Belohlavek M, Khandheria BK. Clinical applications ofstrain rate imaging. J Am Soc Echocardiogr 2003;16:1334–1342.

166. Madler CF, Payne N, Wilkenshoff U, Cohen A, Derumeaux GA, Pierard LAet al. Non-invasive diagnosis of coronary artery disease by quantitativestress echocardiography: optimal diagnostic models using off-line tissueDoppler in the MYDISE study. Eur Heart J 2003;24:1584–1594.

167. Yip G, Khandheria B, Belohlavek M, Pislaru C, Seward J, Bailey K et al.Strain echocardiography tracks dobutamine-induced decrease inregional myocardial perfusion in nonocclusive coronary stenosis. J AmColl Cardiol 2004;44:1664–1671.

168. Marwick TH, Case C, Leano R, Short L, Baglin T, Cain P et al. Use oftissue Doppler imaging to facilitate the prediction of events in patientswith abnormal left ventricular function by dobutamine echocardiogra-phy. Am J Cardiol 2004;93:142–146.

169. Zaret BL, Wackers FJ. Nuclear cardiology (1). N Engl J Med 1993;329:775–783.

170. Zaret BL, Wackers FJ. Nuclear cardiology (2). N Engl J Med 1993;329:855–863.

171. Ritchie JL, Bateman TM, Bonow RO, Crawford MH, Gibbons RJ, Hall RJet al. Guidelines for clinical use of cardiac radionuclide imaging.Report of the American College of Cardiology/American HeartAssociation Task Force on Assessment of Diagnostic and TherapeuticCardiovascular Procedures (Committee on Radionuclide Imaging), devel-oped in collaboration with the American Society of Nuclear Cardiology. JAm Coll Cardiol 1995;25:521–547.

172. Daou D, Delahaye N, Lebtahi R, Vilain D, Peker C, Faraggi M et al.Diagnosis of extensive coronary artery disease: intrinsic value ofincreased lung 201 T1 uptake with exercise SPECT. J Nucl Med2000;41:567–574.

173. Morel O, Pezard P, Furber A, Le Jeune JJ, Vielle B, Denizot B et al.Thallium-201 right lung/heart ratio during exercise in patients with cor-onary artery disease: relation to thallium-201 myocardial single-photonemission tomography, rest and exercise left ventricular function andcoronary angiography. Eur J Nucl Med 1999;26:640–646.

174. Underwood SR, Anagnostopoulos C, Cerqueira M, Ell PJ, Flint EJ,Harbinson M et al. Myocardial perfusion scintigraphy: the evidence.Eur J Nucl Med Mol Imaging 2004;31:261–291.

175. Lette J, Tatum JL, Fraser S, Miller DD, Waters DD, Heller G et al. Safetyof dipyridamole testing in 73,806 patients: the MulticenterDipyridamole Safety Study. J Nucl Cardiol 1995;2:3–17.

176. Cortigiani L, Picano E, Coletta C, Chiarella F, Mathias W, Gandolfo Net al. Safety, feasibility, and prognostic implications of pharmacologicstress echocardiography in 1482 patients evaluated in an ambulatorysetting. Am Heart J 2001;141:621–629.

177. Secknus MA, Marwick TH. Evolution of dobutamine echocardiographyprotocols and indications: safety and side effects in 3,011 studies over5 years. J Am Coll Cardiol 1997;29:1234–1240.

178. Wu JC, Yun JJ, Heller EN, Dione DP, DeMan P, Liu YH et al. Limitations ofdobutamine for enhancing flow heterogeneity in the presence of singlecoronary stenosis: implications for technetium-99m-sestamibi imaging.J Nucl Med 1998;39:417–425.

179. Vigna C, Stanislao M, De Rito V, Russo A, Natali R, Santoro T et al.Dipyridamole stress echocardiography vs. dipyridamole sestamibi scinti-graphy for diagnosing coronary artery disease in left bundle-branchblock. Chest 2001;120:1534–1539.

180. Ciaroni S, Bloch A, Albrecht L, Vanautryve B. Diagnosis of coronaryartery disease in patients with permanent cardiac pacemaker by dobu-tamine stress echocardiography or exercise thallium-201 myocardialtomography. Echocardiography 2000;17:675–679.

181. Alexanderson E, Mannting F, Gomez-Martin D, Fermon S, Meave A.Technetium-99m-Sestamibi SPECT myocardial perfusion imaging inpatients with complete left bundle branch block. Arch Med Res2004;35:150–156.

182. Mairesse GH, Marwick TH, Arnese M, Vanoverschelde JL, Cornel JH,Detry JM et al. Improved identification of coronary artery disease inpatients with left bundle branch block by use of dobutamine stressechocardiography and comparison with myocardial perfusion tomogra-phy. Am J Cardiol 1995;76:321–325.

183. Feola M, Biggi A, Ribichini F, Camuzzini G, Uslenghi E. The diagnosis ofcoronary artery disease in hypertensive patients with chest pain andcomplete left bundle branch block: utility of adenosine Tc-99m tetrofos-min SPECT. Clin Nucl Med 2002;27:510–515.

184. Geleijnse ML, Vigna C, Kasprzak JD, Rambaldi R, Salvatori MP, Elhendy Aet al. Usefulness and limitations of dobutamine-atropine stress echocar-diography for the diagnosis of coronary artery disease in patients withleft bundle branch block. A multicentre study. Eur Heart J2000;21:1666–1673.

185. Vigna C, Stanislao M, De Rito V, Russo A, Santoro T, Fusilli S et al.Inaccuracy of dipyridamole echocardiography or scintigraphy for thediagnosis of coronary artery disease in patients with both left bundlebranch block and left ventricular dysfunction. Int J Cardiol 2005;doi:10.1016/j.ijcard.2005.05.068 [Epub ahead of print July 4, 2005].

186. Cortigiani L, Picano E, Vigna C, Lattanzi F, Coletta C, Mariotti E et al.Prognostic value of pharmacologic stress echocardiography in patientswith left bundle branch block. Am J Med 2001;110:361–369.

187. Underwood SR, Godman B, Salyani S, Ogle JR, Ell PJ. Economics of myo-cardial perfusion imaging in Europe–the EMPIRE Study. Eur Heart J1999;20:157–166.

188. Maddahi J, Iskandrian AE. Cost-effectiveness of nuclear cardiology.J Nucl Cardiol 1997;4:S139–S140.

189. Cerqueira MD. Diagnostic testing strategies for coronary artery disease:special issues related to gender. Am J Cardiol 1995;75:52D–60D.

190. Hachamovitch R, Berman DS, Kiat H, Bairey CN, Cohen I, Cabico A et al.Effective risk stratification using exercise myocardial perfusion SPECT inwomen: gender-related differences in prognostic nuclear testing. J AmColl Cardiol 1996;28:34–44.

191. Marwick TH, Shaw LJ, Lauer MS, Kesler K, Hachamovitch R, Heller GVet al. The noninvasive prediction of cardiac mortality in men andwomen with known or suspected coronary artery disease. Economics ofNoninvasive Diagnosis (END) Study Group. Am J Med 1999;106:172–178.

ESC Guidelines 51

192. Shaw LJ, Hachamovitch R, Redberg RF. Current evidence on diagnostictesting in women with suspected coronary artery disease: choosingthe appropriate test. Cardiol Rev 2000;8:65–74.

193. Elhendy A, van Domburg RT, Bax JJ, Nierop PR, Valkema R, Geleijnse MLet al. Dobutamine-atropine stress myocardial perfusion SPECT imagingin the diagnosis of graft stenosis after coronary artery bypass grafting.J Nucl Cardiol 1998;5:491–497.

194. Lakkis NM, Mahmarian JJ, Verani MS. Exercise thallium-201 singlephoton emission computed tomography for evaluation of coronaryartery bypass graft patency. Am J Cardiol 1995;76:107–111.

195. Shapira I, Heller I, Kornizky Y, Topilsky M, Isakov A. The value of stressthallium-201 single photon emission CT imaging as a predictor ofoutcome and long-term prognosis after CABG. J Med 2001;32:271–282.

196. Lauer MS, Lytle B, Pashkow F, Snader CE, Marwick TH. Prediction ofdeath and myocardial infarction by screening with exercise-thalliumtesting after coronary-artery-bypass grafting. Lancet 1998;351:615–622.

197. Marwick TH, Zuchowski C, Lauer MS, Secknus MA, Williams J, Lytle BW.Functional status and quality of life in patients with heart failure under-going coronary bypass surgery after assessment of myocardial viability.J Am Coll Cardiol 1999;33:750–758.

198. Di Carli MF, Maddahi J, Rokhsar S, Schelbert HR, Bianco-Batlles D,Brunken RC et al. Long-term survival of patients with coronary arterydisease and left ventricular dysfunction: implications for the role ofmyocardial viability assessment in management decisions. J ThoracCardiovasc Surg 1998;116:997–1004.

199. Underwood SR, Bax JJ, vom Dahl J, Henein MY, Knuuti J, van Rossum ACet al. Imaging techniques for the assessment of myocardial hibernation.Report of a Study Group of the European Society of Cardiology. EurHeart J 2004;25:815–836.

200. EL Nagel, Bocksch HB, Klein W, Vogel C, Frantz U, Ellmer E, Dreysse A,Fleck ES. Noninvasive diagnosis of ischemia induced wall motionabnormalities with the use of high dose dobutamine stress MRI.Comparison with dobutamine stress echocardiography. Circulation1999;99:763–770.

201. Hundley WG, Hamilton CA, Clarke GD, Hillis LD, Herrington DM, Lange RAet al. Visualization and functional assessment of proximal and middleleft anterior descending coronary stenoses in humans with magneticresonance imaging. Circulation 1999;99:3248–3254.

202. Hundley WG, Morgan TM, Neagle CM, Hamilton CA, Rerkpattanapipat P,Link KM. Magnetic resonance imaging determination of cardiac progno-sis. Circulation 2002;106:2328–2333.

203. Schwitter J, Nanz D, Kneifel S, Bertschinger K, Buchi M, Knusel PR et al.Assessment of myocardial perfusion in coronary artery disease by mag-netic resonance: a comparison with positron emission tomography andcoronary angiography. Circulation 2001;103:2230–2235.

204. Ishida N, Sakuma H, Motoyasu M, Okinaka T, Isaka N, Nakano T et al.Noninfarcted myocardium: correlation between dynamic first-passcontrast-enhanced myocardial MR imaging and quantitative coronaryangiography. Radiology 2003;229:209–216.

205. Pennell DJ, Sechtem UP, Higgins CB, Manning WJ, Pohost GM,Rademakers FE et al. Clinical indications for cardiovascular magneticresonance (CMR): Consensus Panel report. Eur Heart J 2004;25:1940–1965.

206. Xu M, McHaffie DJ. Nonspecific systolic murmurs: an audit of the clinicalvalue of echocardiography. N Z Med J 1993;106:54–56.

207. Nagueh SF, Bachinski LL, Meyer D, Hill R, Zoghbi WA, Tam JW et al.Tissue Doppler imaging consistently detects myocardial abnormalitiesin patients with hypertrophic cardiomyopathy and provides a novelmeans for an early diagnosis before and independently of hypertrophy.Circulation 2001;104:128–130.

208. Hoffmann A, Burckhardt D. Evaluation of systolic murmurs by Dopplerultrasonography. Br Heart J 1983;50:337–342.

209. Attenhofer Jost CH, Turina J, Mayer K, Seifert B, Amann FW, Buechi Met al. Echocardiography in the evaluation of systolic murmurs ofunknown cause. Am J Med 2000;108:614–620.

210. Fink JC, Schmid CH, Selker HP. A decision aid for referring patients withsystolic murmurs for echocardiography. J Gen Intern Med 1994;9:479–484.

211. McKillop GM, Stewart DA, Burns JM, Ballantyne D. Doppler echocardio-graphy in elderly patients with ejection systolic murmurs. PostgradMed J 1991;67:1059–1061.

212. Rakowski H, Sasson Z, Wigle ED. Echocardiographic and Doppler assess-ment of hypertrophic cardiomyopathy. J Am Soc Echocardiogr1988;1:31–47.

213. Shaw LJ, Peterson ED, Kesler K, Hasselblad V, Califf RM. A metaanalysisof predischarge risk stratification after acute myocardial infarction withstress electrocardiographic, myocardial perfusion, and ventricular func-tion imaging. Am J Cardiol 1996;78:1327–1337.

214. Marchioli R, Avanzini F, Barzi F, Chieffo C, Di Castelnuovo A, Franzosi MGet al. Assessment of absolute risk of death after myocardial infarctionby use of multiple-risk-factor assessment equations: GISSI-Prevenzionemortality risk chart. Eur Heart J 2001;22:2085–2103.

215. Echeverria HH, Bilsker MS, Myerburg RJ, Kessler KM. Congestive heartfailure: echocardiographic insights. Am J Med 1983;75:750–755.

216. Aguirre FV, Pearson AC, Lewen MK, McCluskey M, Labovitz AJ. Usefulnessof Doppler echocardiography in the diagnosis of congestive heartfailure. Am J Cardiol 1989;63:1098–1102.

217. Shah PM. Echocardiography in congestive or dilated cardiomyopathy.J Am Soc Echocardiogr 1988;1:20–30.

218. Rihal CS, Nishimura RA, Hatle LK, Bailey KR, Tajik AJ. Systolic and dia-stolic dysfunction in patients with clinical diagnosis of dilated cardio-myopathy. Relation to symptoms and prognosis. Circulation 1994;90:2772–2779.

219. Fonseca C, Mota T, Morais H, Matias F, Costa C, Oliveira AG et al. Thevalue of the electrocardiogram and chest X-ray for confirming or refut-ing a suspected diagnosis of heart failure in the community. Eur J HeartFail 2004;6:807–812.

220. Vasan RS, Benjamin EJ, Levy D. Prevalence, clinical features and prog-nosis of diastolic heart failure: an epidemiologic perspective. J Am CollCardiol 1995;26:1565–1574.

221. O’Mahony MS, Sim MF, Ho SF, Steward JA, Buchalter M, Burr M. Diastolicheart failure in older people. Age Ageing 2003;32:519–524.

222. Mottram PM, Marwick TH. Assessment of diastolic function: what thegeneral cardiologist needs to know. Heart 2005;91:681–695.

223. Zaliunas R, Jurkevicus R, Zabiela V, Brazdzionyte J. Effect of amlodipineand lacidipine on left ventricular diastolic and long axis functions inarterial hypertension and stable angina pectoris. Acta Cardiol2005;60:239–246.

224. Gill JB, Cairns JA, Roberts RS, Costantini L, Sealey BJ, Fallen EF et al.Prognostic importance of myocardial ischemia detected by ambulatorymonitoring early after acute myocardial infarction. N Engl J Med1996;334:65–70.

225. Ambrose JA, Fuster V. Can we predict future acute coronary events inpatients with stable coronary artery disease? JAMA 1997;277:343–344.

226. Mulcahy D, Knight C, Patel D, Curzen N, Cunningham D, Wright C et al.Detection of ambulatory ischaemia is not of practical clinical value inthe routine management of patients with stable angina. A long-termfollow-up study. Eur Heart J 1995;16:317–324.

227. Knez A, Becker A, Leber A, White C, Becker CR, Reiser MF et al. Relationof coronary calcium scores by electron beam tomography to obstructivedisease in 2,115 symptomatic patients. Am J Cardiol 2004;93:1150–1152.

228. Becker CR. Noninvasive assessment of coronary atherosclerosis bymultidetector-row computed tomography. Expert Rev Cardiovasc Ther2004;2:721–727.

229. Stanford W, Thompson BH, Burns TL, Heery SD, Burr MC. Coronary arterycalcium quantification at multi-detector row helical CT versuselectron-beam CT. Radiology 2004;230:397–402.

230. Nasir K, Budoff MJ, Post WS, Fishman EK, Mahesh M, Lima JA et al.Electron beam CT versus helical CT scans for assessing coronary calcifi-cation: current utility and future directions. Am Heart J2003;146:969–977.

231. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M Jr,Detrano R. Quantification of coronary artery calcium using ultrafastcomputed tomography. J Am Coll Cardiol 1990;15:827–832.

232. Hoff JA, Chomka EV, Krainik AJ, Daviglus M, Rich S, Kondos GT. Age andgender distributions of coronary artery calcium detected by electronbeam tomography in 35,246 adults. Am J Cardiol 2001;87:1335–1339.

233. Rumberger JA, Simons DB, Fitzpatrick LA, Sheedy PF, Schwartz RS.Coronary artery calcium area by electron-beam computed tomographyand coronary atherosclerotic plaque area. A histopathologic correlativestudy. Circulation 1995;92:2157–2162.

234. O’Rourke RA, Brundage BH, Froelicher VF, Greenland P, Grundy SM,Hachamovitch R et al. American College of Cardiology/AmericanHeart Association Expert Consensus Document on electron-beam com-puted tomography for the diagnosis and prognosis of coronary arterydisease. J Am Coll Cardiol 2000;36:326–340.

235. Daly C, Saravanan P, Fox K. Is calcium the clue? Eur Heart J2002;23:1562–1565.

52 ESC Guidelines

236. de Feyter PJ, Nieman K. Noninvasive multi-slice computed tomographycoronary angiography: an emerging clinical modality. J Am Coll Cardiol2004;44:1238–1240.

237. Hoffmann MH, Shi H, Schmitz BL, Schmid FT, Lieberknecht M, Schulze Ret al. Noninvasive coronary angiography with multislice computed tom-ography. JAMA 2005;293:2471–2478.

238. Raff GL, Gallagher MJ, O’Neill WW, Goldstein JA. Diagnostic accuracy ofnoninvasive coronary angiography using 64-slice spiral computed tom-ography. J Am Coll Cardiol 2005;46:552–557.

239. Leschka S, Alkadhi H, Plass A, Desbiolles L, Grunenfelder J, Marincek Bet al. Accuracy of MSCT coronary angiography with 64-slice technology:first experience. Eur Heart J 2005;26:1482–1487.

240. Toussaint JF, LaMuraglia GM, Southern JF, Fuster V, Kantor HL. Magneticresonance images lipid, fibrous, calcified, hemorrhagic, and thromboticcomponents of human atherosclerosis in vivo. Circulation1996;94:932–938.

241. Spaulding CM, Joly LM, Rosenberg A, Monchi M, Weber SN, Dhainaut JFet al. Immediate coronary angiography in survivors of out-of-hospitalcardiac arrest. N Engl J Med 1997;336:1629–1633.

242. Borger van der Burg AE, Bax JJ, Boersma E, Bootsma M, van Erven L, vander Wall EE et al. Impact of percutaneous coronary intervention or cor-onary artery bypass grafting on outcome after nonfatal cardiac arrestoutside the hospital. Am J Cardiol 2003;91:785–789.

243. Noto TJ Jr, Johnson LW, Krone R, Weaver WF, Clark DA, Kramer JR Jret al. Cardiac catheterization 1990: a report of the Registry of theSociety for Cardiac Angiography and Interventions (SCA&I). CatheterCardiovasc Diagn 1991;24:75–83.

244. Yock PG, Linker DT, Angelsen BA. Two-dimensional intravascular ultra-sound: technical development and initial clinical experience. J AmSoc Echocardiogr 1989;2:296–304.

245. Di Mario C, Gorge G, Peters R, Kearney P, Pinto F, Hausmann D et al.Clinical application and image interpretation in intracoronary ultra-sound. Study Group on Intracoronary Imaging of the Working Group ofCoronary Circulation and of the Subgroup on Intravascular Ultrasoundof the Working Group of Echocardiography of the European Society ofCardiology. Eur Heart J 1998;19:207–229.

246. Mintz GS, Nissen SE, Anderson WD, Bailey SR, Erbel R, Fitzgerald PJet al. American College of Cardiology Clinical Expert ConsensusDocument on Standards for Acquisition, Measurement and Reporting ofIntravascular Ultrasound Studies (IVUS). A report of the AmericanCollege of Cardiology Task Force on Clinical Expert ConsensusDocuments. J Am Coll Cardiol 2001;37:1478–1492.

247. Di Carli M, Czernin J, Hoh CK, Gerbaudo VH, Brunken RC, Huang SC et al.Relation among stenosis severity, myocardial blood flow, and flowreserve in patients with coronary artery disease. Circulation1995;91:1944–1951.

248. Pijls NH, De Bruyne B, Peels K, Van Der Voort PH, Bonnier HJ,Bartunek JKJJ et al. Measurement of fractional flow reserve to assessthe functional severity of coronary-artery stenoses. N Engl J Med1996;334:1703–1708.

249. Legalery P, Schiele F, Seronde MF, Meneveau N, Wei H, Didier K et al.1 year outcome of patients submitted to routine fractional flowreserve assessment to determine the need for angioplasty. Eur Heart J2005;26:2623–2629.

250. De Backer G, Ambrosioni E, Borch-Johnsen K, Brotons C, Cifkova R,Dallongeville J et al. European guidelines on cardiovascular disease pre-vention in clinical practice. Third Joint Task Force of European andOther Societies on Cardiovascular Disease Prevention in ClinicalPractice. Eur Heart J 2003;24:1601–1610.

251. Hense HW. Risk factor scoring for coronary heart disease. BMJ2003;327:1238–1239.

252. Braunwald E, Domanski MJ, Fowler SE, Geller NL, Gersh BJ, Hsia J et al.Angiotensin-converting-enzyme inhibition in stable coronary arterydisease. N Engl J Med 2004;351:2058–2068.

253. Heart Outcomes Prevention Evaluation Study Investigators. Effects oframipril on cardiovascular and microvascular outcomes in people withdiabetes mellitus: results of the HOPE study and MICRO-HOPE substudy.Lancet 2000;355:253–259.

254. Effect of nicorandil on coronary events in patients with stable angina:the Impact Of Nicorandil in Angina (IONA) randomised trial. Lancet2002;359:1269–1275.

255. Califf RM, Mark DB, Harrell FE Jr, Hlatky MA, Lee KL, Rosati RA et al.Importance of clinical measures of ischemia in the prognosis of patientswith documented coronary artery disease. J Am Coll Cardiol1988;11:20–26.

256. Proudfit WL, Kramer JR, Bott-Silverman C, Goormastic M. Survival ofnon-surgical patients with mild angina or myocardial infarctionwithout angina. Br Heart J 1986;56:213–221.

257. Schlant RC, Forman S, Stamler J, Canner PL. The natural history of cor-onary heart disease: prognostic factors after recovery from myocardialinfarction in 2789 men. The 5-year findings of the coronary drug project.Circulation 1982;66:401–414.

258. Phillips AN, Shaper AG, Pocock SJ, Walker M, Macfarlane PW. The role ofrisk factors in heart attacks occurring in men with pre-existing ischae-mic heart disease. Br Heart J 1988;60:404–410.

259. Brewer HB Jr. Hypertriglyceridemia: changes in the plasma lipoproteinsassociated with an increased risk of cardiovascular disease. Am J Cardiol1999;83:3F–12F.

260. Hultgren HN, Peduzzi P. Relation of severity of symptoms to prognosis instable angina pectoris. Am J Cardiol 1984;54:988–993.

261. Pryor DB, Shaw L, McCants CB, Lee KL, Mark DB, Harrell FE Jr et al.Value of the history and physical in identifying patients at increasedrisk for coronary artery disease. Ann Intern Med 1993;118:81–90.

262. Papamichael CM, Lekakis JP, Stamatelopoulos KS, Papaioannou TG,Alevizaki MK, Cimponeriu AT et al. Ankle-brachial index as a predictorof the extent of coronary atherosclerosis and cardiovascular events inpatients with coronary artery disease. Am J Cardiol 2000;86:615–618.

263. Eagle KA, Rihal CS, Foster ED, Mickel MC, Gersh BJ. Long-term survivalin patients with coronary artery disease: importance of peripheral vas-cular disease. The Coronary Artery Surgery Study (CASS) Investigators. JAm Coll Cardiol 1994;23:1091–1095.

264. Kannel WB, Abbott RD. A prognostic comparison of asymptomatic leftventricular hypertrophy and unrecognized myocardial infarction: theFramingham Study. Am Heart J 1986;111:391–397.

265. Sullivan JM, Vander Zwaag RV, el-Zeky F, Ramanathan KB, Mirvis DM. Leftventricular hypertrophy: effect on survival. J Am Coll Cardiol1993;22:508–513.

266. Block WJ Jr, Crumpacker EL, Dry TJ, Gage RP. Prognosis of angina pec-toris; observations in 6,882 cases. J Am Med Assoc 1952;150:259–264.

267. Biagini E, Elhendy A, Schinkel AF, Nelwan S, Rizzello V, van Domburg RTet al. Prognostic significance of left anterior hemiblock in patients withsuspected coronary artery disease. J Am Coll Cardiol 2005;46:858–863.

268. Morris CK, Ueshima K, Kawaguchi T, Hideg A, Froelicher VF. The prognos-tic value of exercise capacity: a review of the literature. Am Heart J1991;122:1423–1431.

269. Dagenais GR, Rouleau JR, Christen A, Fabia J. Survival of patients with astrongly positive exercise electrocardiogram. Circulation 1982;65:452–456.

270. McNeer JF, Margolis JR, Lee KL, Kisslo JA, Peter RH, Kong Y et al. Therole of the exercise test in the evaluation of patients for ischaemicheart disease. Circulation 1978;57:64–70.

271. Morrow K, Morris CK, Froelicher VF, Hideg A, Hunter D, Johnson E et al.Prediction of cardiovascular death in men undergoing noninvasive evalu-ation for coronary artery disease. Ann Intern Med 1993;118:689–695.

272. Mark DB, Hlatky MA, Harrell FE Jr, Lee KL, Califf RM, Pryor DB. Exercisetreadmill score for predicting prognosis in coronary artery disease. AnnIntern Med 1987;106:793–800.

273. Prakash M, Myers J, Froelicher VF, Marcus R, Do D, Kalisetti D et al. Clinicaland exercise test predictors of all-cause mortality: results from .6,000consecutive referred male patients. Chest 2001;120:1003–1013.

274. Marwick TH, Mehta R, Arheart K, Lauer MS. Use of exercise echocardio-graphy for prognostic evaluation of patients with known or suspectedcoronary artery disease. J Am Coll Cardiol 1997;30:83–90.

275. Geleijnse ML, Elhendy A, van Domburg RT, Cornel JH, Rambaldi R, SalustriA et al. Cardiac imaging for risk stratification with dobutamine-atropinestress testing in patients with chest pain. Echocardiography, perfusionscintigraphy, or both? Circulation 1997;96:137–147.

276. Olmos LI, Dakik H, Gordon R, Dunn JK, Verani MS, Quinones MA et al.Long-term prognostic value of exercise echocardiography comparedwith exercise 201Tl, ECG, and clinical variables in patients evaluatedfor coronary artery disease. Circulation 1998;98:2679–2686.

277. Brown KA. Prognostic value of thallium-201 myocardial perfusionimaging. A diagnostic tool comes of age. Circulation 1991;83:363–381.

278. Hachamovitch R, Berman DS, Shaw LJ, Kiat H, Cohen I, Cabico JA et al.Incremental prognostic value of myocardial perfusion single photonemission computed tomography for the prediction of cardiac death:differential stratification for risk of cardiac death and myocardialinfarction. Circulation 1998;97:535–543.

279. McClellan JR, Travin MI, Herman SD, Baron JI, Golub RJ, Gallagher JJet al. Prognostic importance of scintigraphic left ventricular cavitydilation during intravenous dipyridamole technetium-99m sestamibi

ESC Guidelines 53

myocardial tomographic imaging in predicting coronary events. Am JCardiol 1997;79:600–605.

280. Emond M, Mock MB, Davis KB, Fisher LD, Holmes DR Jr, Chaitman BRet al. Long-term survival of medically treated patients in theCoronary Artery Surgery Study (CASS) Registry. Circulation1994;90:2645–2657.

281. McDonagh TA, Morrison CE, Lawrence A, Ford I, Tunstall-Pedoe H,McMurray JJ et al. Symptomatic and asymptomatic left-ventricular sys-tolic dysfunction in an urban population. Lancet 1997;350:829–833.

282. Raymond I, Pedersen F, Steensgaard-Hansen F, Green A, Busch-Sorensen M,Tuxen C et al. Prevalence of impaired left ventricular systolic function andheart failure in a middle aged and elderly urban population segment ofCopenhagen. Heart 2003;89:1422–1429.

283. Mosterd A, Hoes AW, de Bruyne MC, Deckers JW, Linker DT, Hofman Aet al. Prevalence of heart failure and left ventricular dysfunction inthe general population; The Rotterdam Study. Eur Heart J1999;20:447–455.

284. Daly C, Norrie J, Murdoch DL, Ford I, Dargie HJ, Fox K. The value ofroutine non-invasive tests to predict clinical outcome in stableangina. Eur Heart J 2003;24:532–540.

285. Cuspidi C, Ambrosioni E, Mancia G, Pessina AC, Trimarco B, Zanchetti A.Role of echocardiography and carotid ultrasonography in stratifying riskin patients with essential hypertension: the Assessment of PrognosticRisk Observational Survey. J Hypertens 2002;20:1307–1314.

286. European Society of Hypertension and the European Society of Cardiol-ogy. European Society of Hypertension–European Society of Cardiologyguidelines for the management of arterial hypertension. J Hypertens2003;21:1011–1053.

287. European Coronary Surgery Study Group. Long-term results of prospec-tive randomised study of coronary artery bypass surgery in stable anginapectoris. Lancet 1982;2:1173–1180.

288. Mark DB, Nelson CL, Califf RM, Harrell FE Jr, Lee KL, Jones RH et al.Continuing evolution of therapy for coronary artery disease. Initialresults from the era of coronary angioplasty. Circulation1994;89:2015–2025.

289. Nakagomi A, Celermajer DS, Lumley T, Freedman SB. Angiographicseverity of coronary narrowing is a surrogate marker for the extent ofcoronary atherosclerosis. Am J Cardiol 1996;78:516–519.

290. Rihal CS, Raco DL, Gersh BJ, Yusuf S. Indications for coronary arterybypass surgery and percutaneous coronary intervention in chronicstable angina: review of the evidence and methodological consider-ations. Circulation 2003;108:2439–2445.

291. Kennedy JW, Killip T, Fisher LD, Alderman EL, Gillespie MJ, Mock MB.The clinical spectrum of coronary artery disease and its surgical andmedical management, 1974–1979. The Coronary Artery Surgery study.Circulation 1982;66:III16–III23.

292. Kemp HG Jr. Left ventricular function in patients with the anginal syn-drome and normal coronary arteriograms. Am J Cardiol1973;32:375–376.

293. Cosin-Sales J, Pizzi C, Brown S, Kaski JC. C-reactive protein, clinicalpresentation, and ischaemic activity in patients with chest pain andnormal coronary angiograms. J Am Coll Cardiol 2003;41:1468–1474.

294. Cannon RO III, Epstein SE. ‘Microvascular angina’ as a cause of chestpain with angiographically normal coronary arteries. Am J Cardiol1988;61:1338–1343.

295. Luscher TF. The endothelium and cardiovascular disease–a complexrelation. N Engl J Med 1994;330:1081–1083.

296. Oki T, Tabata T, Yamada H, Wakatsuki T, Mishiro Y, Abe M et al. Left ven-tricular diastolic properties of hypertensive patients measured bypulsed tissue Doppler imaging. J Am Soc Echocardiogr1998;11:1106–1112.

297. Diamond JA, Phillips RA. Hypertensive heart disease. Hypertens Res2005;28:191–202.

298. Schafer S, Kelm M, Mingers S, Strauer BE. Left ventricular remodelingimpairs coronary flow reserve in hypertensive patients. J Hypertens2002;20:1431–1437.

299. Preik M, Kelm M, Strauer BE. Management of the hypertensive patientwith coronary insufficiency but without atherosclerosis. Curr OpinCardiol 2003;18:255–259.

300. Cannon RO III, Camici PG, Epstein SE. Pathophysiological dilemma ofsyndrome X. Circulation 1992;85:883–892.

301. Panza JA, Laurienzo JM, Curiel RV, Unger EF, Quyyumi AA, Dilsizian Vet al. Investigation of the mechanism of chest pain in patients withangiographically normal coronary arteries using transesophageal dobu-tamine stress echocardiography. J Am Coll Cardiol 1997;29:293–301.

302. Chauhan A, Mullins PA, Thuraisingham SI, Taylor G, Petch MC, Schofield PM.Abnormal cardiac pain perception in syndrome X. J Am Coll Cardiol1994;24:329–335.

303. Kaski JC, Rosano GM, Collins P, Nihoyannopoulos P, Maseri A, Poole-Wilson PA. Cardiac syndrome X: clinical characteristics and left ventri-cular function. Long-term follow-up study. J Am Coll Cardiol1995;25:807–814.

304. Atienza F, Velasco JA, Brown S, Ridocci F, Kaski JC. Assessment of qualityof life in patients with chest pain and normal coronary arteriogram (syn-drome X) using a specific questionnaire. Clin Cardiol 1999;22:283–290.

305. Bugiardini R, Bairey Merz CN. Angina with ‘normal’ coronary arteries: achanging philosophy. JAMA 2005;293:477–484.

306. Johnson BD, Shaw LJ, Buchthal SD, Bairey Merz CN, Kim HW, Scott KNet al. Prognosis in women with myocardial ischemia in the absence ofobstructive coronary disease: results from the National Institutes ofHealth-National Heart, Lung, and Blood Institute-Sponsored Women’sIschemia Syndrome Evaluation (WISE). Circulation 2004;109:2993–2999.

307. Bugiardini R, Manfrini O, Pizzi C, Fontana F, Morgagni G. Endothelialfunction predicts future development of coronary artery disease: astudy of women with chest pain and normal coronary angiograms.Circulation 2004;109:2518–2523.

308. Halcox JP, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MAet al. Prognostic value of coronary vascular endothelial dysfunction.Circulation 2002;106:653–658.

309. Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR Jr, LermanA. Long-term follow-up of patients with mild coronary artery diseaseand endothelial dysfunction. Circulation 2000;101:948–954.

310. von Mering GO, Arant CB, Wessel TR, McGorray SP, Bairey Merz CN,Sharaf BL et al. Abnormal coronary vasomotion as a prognostic indicatorof cardiovascular events in women: results from the National Heart,Lung, and Blood Institute-Sponsored Women’s Ischemia SyndromeEvaluation (WISE). Circulation 2004;109:722–725.

311. Hillis LD, Braunwald E. Coronary-artery spasm. N Engl J Med1978;299:695–702.

312. Prinzmetal M, Kennamer R, Merliss R, Wada T, Bor N. Anginapectoris. I. A variant form of angina pectoris; preliminary report. AmJ Med 1959;27:375–388.

313. Maseri A, Severi S, Nes MD, L’Abbate A, Chierchia S, Marzilli M et al.‘Variant’ angina: one aspect of a continuous spectrum of vasospasticmyocardial ischemia. Pathogenetic mechanisms, estimated incidenceand clinical and coronary arteriographic findings in 138 patients. Am JCardiol 1978;42:1019–1035.

314. Bugiardini R, Pozzati A, Ottani F, Morgagni GL, Puddu P. Vasotonicangina: a spectrum of ischaemic syndromes involving functionalabnormalities of the epicardial and microvascular coronary circulation.J Am Coll Cardiol 1993;22:417–425.

315. Kaski JC, Crea F, Meran D, Rodriguez L, Araujo L, Chierchia S et al. Localcoronary supersensitivity to diverse vasoconstrictive stimuli in patientswith variant angina. Circulation 1986;74:1255–1265.

316. Nakayama M, Yasue H, Yoshimura M, Shimasaki Y, Kugiyama K, Ogawa Het al. T-786–.C mutation in the 5’-flanking region of the endothelialnitric oxide synthase gene is associated with coronary spasm.Circulation 1999;99:2864–2870.

317. Kugiyama K, Yasue H, Okumura K, Ogawa H, Fujimoto K, Nakao K et al.Nitric oxide activity is deficient in spasm arteries of patients with coro-nary spastic angina. Circulation 1996;94:266–271.

318. Masumoto A, Mohri M, Shimokawa H, Urakami L, Usui M, Takeshita A.Suppression of coronary artery spasm by the Rho-kinase inhibitorfasudil in patients with vasospastic angina. Circulation 2002;105:1545–1547.

319. Chutkow WA, Pu J, Wheeler MT, Wada T, Makielski JC, Burant CF et al.Episodic coronary artery vasospasm and hypertension develop in theabsence of Sur2 K(ATP) channels. J Clin Invest 2002;110:203–208.

320. Lanza GA, De Candia E, Romagnoli E, Messano L, Sestito A, Landolfi Ret al. Increased platelet sodium-hydrogen exchanger activity in patientswith variant angina. Heart 2003;89:935–936.

321. Takusagawa M, Komori S, Umetani K, Ishihara T, Sawanobori T, Kohno Iet al. Alterations of autonomic nervous activity in recurrence ofvariant angina. Heart 1999;82:75–81.

322. Lanza GA, Pedrotti P, Pasceri V, Lucente M, Crea F, Maseri A. Autonomicchanges associated with spontaneous coronary spasm in patients withvariant angina. J Am Coll Cardiol 1996;28:1249–1256.

323. Luscher TF, Noll G. Is it all in the genes? Nitric oxide synthase and cor-onary vasospasm. Circulation 1999;99:2855–2857.

54 ESC Guidelines

324. Hermsmeyer K, Miyagawa K, Kelley ST, Rosch J, Hall AS, Axthelm MKet al. Reactivity-based coronary vasospasm independent of athero-sclerosis in rhesus monkeys. J Am Coll Cardiol 1997;29:671–680.

325. Minshall RD, Stanczyk FZ, Miyagawa K, Uchida B, Axthelm M, Novy Met al. Ovarian steroid protection against coronary artery hyperreactivityin rhesus monkeys. J Clin Endocrinol Metab 1998;83:649–659.

326. MacAlpin RN. Cardiac arrest and sudden unexpected death in variantangina: complications of coronary spasm that can occur in theabsence of severe organic coronary stenosis. Am Heart J1993;125:1011–1017.

327. Yamagishi M, Ito K, Tsutsui H, Miyazaki S, Goto Y, Nagaya N et al. Lesionseverity and hypercholesterolemia determine long-term prognosis ofvasospastic angina treated with calcium channel antagonists. Circ J2003;67:1029–1035.

328. Bory M, Pierron F, Panagides D, Bonnet JL, Yvorra S, Desfossez L.Coronary artery spasm in patients with normal or near normal coronaryarteries. Long-term follow-up of 277 patients. Eur Heart J1996;17:1015–1021.

329. Nakamura M, Takeshita A, Nose Y. Clinical characteristics associatedwith myocardial infarction, arrhythmias, and sudden death in patientswith vasospastic angina. Circulation 1987;75:1110–1116.

330. Walling A, Waters DD, Miller DD, Roy D, Pelletier GB, TherouxP. Long-term prognosis of patients with variant angina. Circulation1987;76:990–997.

331. Yasue H, Takizawa A, Nagao M, Nishida S, Horie M, Kubota J et al. Long-term prognosis for patients with variant angina and influential factors.Circulation 1988;78:1–9.

332. Mark DB, Califf RM, Morris KG, Harrell FE Jr, Pryor DB, Hlatky MA et al.Clinical characteristics and long-term survival of patients with variantangina. Circulation 1984;69:880–888.

333. Matsubara T, Tamura Y, Yamazoe M, Hori T, Konno T, Ida T et al.Correlation between arteriographic and electrocardiographic featuresduring spasm in the left anterior descending coronary artery. CoronArtery Dis 1997;8:525–535.

334. Koh KK, Moon TH, Song JH, Park GS, Lee KH, Cho SK et al. Comparison ofclinical and laboratory findings between patients with diffuse three-vessel coronary artery spasm and other types of coronary arteryspasm. Catheter Cardiovasc Diagn 1996;37:132–139.

335. Sueda S, Kohno H, Fukuda H, Inoue K, Suzuki J, Watanabe K et al.Clinical and angiographical characteristics of acetylcholine- inducedspasm: relationship to dose of intracoronary injection of acetylcholine.Coron Artery Dis 2002;13:231–236.

336. Onaka H, Hirota Y, Shimada S, Kita Y, Sakai Y, Kawakami Y et al. Clinicalobservation of spontaneous anginal attacks and multivessel spasm invariant angina pectoris with normal coronary arteries: evaluation by24-hour 12-lead electrocardiography with computer analysis. J AmColl Cardiol 1996;27:38–44.

337. Bertrand ME, Lablanche JM, Tilmant PY. Use of provocative testing inangina pectoris. Herz 1980;5:65–71.

338. Sueda S, Saeki H, Otani T, Ochi N, Kukita H, Kawada H et al.Investigation of the most effective provocation test for patients withcoronary spastic angina: usefulness of accelerated exercise followinghyperventilation. Jpn Circ J 1999;63:85–90.

339. Yasue H, Horio Y, Nakamura N, Fujii H, Imoto N, Sonoda R et al.Induction of coronary artery spasm by acetylcholine in patients withvariant angina: possible role of the parasympathetic nervous system inthe pathogenesis of coronary artery spasm. Circulation1986;74:955–963.

340. Sueda S, Kohno H, Fukuda H, Watanabe K, Ochi N, Kawada H et al.Limitations of medical therapy in patients with pure coronary spasticangina. Chest 2003;123:380–386.

341. Sueda S, Kohno H, Fukuda H, Ochi N, Kawada H, Hayashi Y et al.Frequency of provoked coronary spasms in patients undergoing coronaryarteriography using a spasm provocation test via intracoronary adminis-tration of ergonovine. Angiology 2004;55:403–411.

342. Maseri A, Davies G, Hackett D, Kaski JC. Coronary artery spasm andvasoconstriction. The case for a distinction. Circulation 1990;81:1983–1991.

343. Mohri M, Koyanagi M, Egashira K, Tagawa H, Ichiki T, Shimokawa H et al.Angina pectoris caused by coronary microvascular spasm. Lancet1998;351:1165–1169.

344. Pristipino C, Beltrame JF, Finocchiaro ML, Hattori R, Fujita M, MongiardoR et al. Major racial differences in coronary constrictor responsebetween japanese and caucasians with recent myocardial infarction.Circulation 2000;101:1102–1108.

345. Sueda S, Saeki H, Otani T, Mineoi K, Kondou T, Yano K et al. Majorcomplications during spasm provocation tests with an intracoronaryinjection of acetylcholine. Am J Cardiol 2000;85:391–394. A10.

346. Song JK, Park SW, Kim JJ, Doo YC, Kim WH, Park SJ et al. Values of intra-venous ergonovine test with two-dimensional echocardiography fordiagnosis of coronary artery spasm. J Am Soc Echocardiogr1994;7:607–615.

347. Morales MA, Lombardi M, Distante A, Carpeggiani C, Reisenhofer B,L’Abbate A. Ergonovine-echo test to assess the significance of chestpain at rest without ECG changes. Eur Heart J 1995;16:1361–1366.

348. Buxton A, Goldberg S, Hirshfeld JW, Wilson J, Mann T, Williams DO et al.Refractory ergonovine-induced coronary vasospasm: importance ofintracoronary nitroglycerin. Am J Cardiol 1980;46:329–334.

349. Mosca L, Appel LJ, Benjamin EJ, Berra K, Chandra-Strobos N, Fabunmi RPet al. Evidence-based guidelines for cardiovascular disease prevention inwomen. Circulation 2004;109:672–693.

350. Bartecchi CE, MacKenzie TD, Schrier RW. The human costs of tobaccouse (1). N Engl J Med 1994;330:907–912.

351. MacKenzie TD, Bartecchi CE, Schrier RW. The human costs of tobaccouse (2). N Engl J Med 1994;330:975–980.

352. Benowitz NL, Gourlay SG. Cardiovascular toxicity of nicotine: impli-cations for nicotine replacement therapy. J Am Coll Cardiol1997;29:1422–1431.

353. Tzivoni D, Keren A, Meyler S, Khoury Z, Lerer T, Brunel P. Cardiovascularsafety of transdermal nicotine patches in patients with coronary arterydisease who try to quit smoking. Cardiovasc Drugs Ther 1998;12:239–244.

354. Working Group for the Study of Transdermal Nicotine in Patients withCoronary artery disease. Nicotine replacement therapy for patientswith coronary artery disease. Arch Intern Med 1994;154:989–995.

355. Critchley J, Capewell S. Smoking cessation for the secondary preventionof coronary heart disease. Cochrane Database Syst Rev 2003, Issue 4.Art. No.: CD003041, doi: 10.1002/14651858.CD003041.pub2.

356. Smith GD, Shipley MJ, Marmot MG, Rose G. Plasma cholesterol concen-tration and mortality. The Whitehall Study. JAMA 1992;267:70–76.

357. Doll R, Peto R, Hall E, Wheatley K, Gray R. Alcohol and coronary heartdisease reduction among British doctors: confounding or causality?Eur Heart J 1997;18:23–25.

358. Di Castelnuovo A, Rotondo S, Iacoviello L, Donati MB, De Gaetano G.Meta-analysis of wine and beer consumption in relation to vascularrisk. Circulation 2002;105:2836–2844.

359. Sesso HD, Stampfer MJ, Rosner B, Hennekens CH, Manson JE, Gaziano JM.7 year changes in alcohol consumption and subsequent risk of cardiovas-cular disease in men. Arch Intern Med 2000;160:2605–2612.

360. Goldberg IJ, Mosca L, Piano MR, Fisher EA. AHA Science Advisory: Wineand your heart: a science advisory for healthcare professionals from theNutrition Committee, Council on Epidemiology and Prevention, andCouncil on Cardiovascular Nursing of the American Heart Association.Circulation 2001;103:472–475.

361. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto mio-cardico. Dietary supplementation with n-3 polyunsaturated fatty acidsand vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 1999;354:447–455.

362. Marchioli R, Barzi F, Bomba E, Chieffo C, Di Gregorio D, Di Mascio R et al.Early protection against sudden death by n-3 polyunsaturated fattyacids after myocardial infarction: time-course analysis of the resultsof the Gruppo Italiano per lo Studio della Sopravvivenza nell’InfartoMiocardico (GISSI)-Prevenzione. Circulation 2002;105:1897–1903.

363. Bucher HC, Hengstler P, Schindler C, Meier G. N-3 polyunsaturated fattyacids in coronary heart disease: a meta-analysis of randomized con-trolled trials. Am J Med 2002;112:298–304.

364. Studer M, Briel M, Leimenstoll B, Glass TR, Bucher HC. Effect of differ-ent antilipidemic agents and diets on mortality: a systematic review.Arch Intern Med 2005;165:725–730.

365. Kris-Etherton PM, Harris WS, Appel LJ. Fish consumption, fish oil,omega-3 fatty acids, and cardiovascular disease. Arterioscler ThrombVasc Biol 2003;23:e20–e30.

366. He K, Song Y, Daviglus ML, Liu K, Van Horn L, Dyer AR et al. Accumulatedevidence on fish consumption and coronary heart disease mortality: ameta-analysis of cohort studies. Circulation 2004;109:2705–2711.

367. Heart Protection Study Collaborative Group. MRC/BHF Heart ProtectionStudy of antioxidant vitamin supplementation in 20,536 high-risk indi-viduals: a randomised placebo-controlled trial. Lancet 2002;360:23–33.

368. Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplemen-tation and cardiovascular events in high-risk patients. The Heart

ESC Guidelines 55

Outcomes Prevention Evaluation Study Investigators. N Engl J Med2000;342:154–160.

369. Kris-Etherton PM, Lichtenstein AH, Howard BV, Steinberg D, Witztum JL.Antioxidant vitamin supplements and cardiovascular disease.Circulation 2004;110:637–641.

370. American Diabetes Association. Standards of medical care for patientswith diabetes mellitus. Diabetes Care 2003;26(Suppl. 1):s33–s50.

371. Inzucchi SE, Amatruda JM. Lipid management in patients with diabetes:translating guidelines into action. Diabetes Care 2003;26:1309–1311.

372. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O.Multifactorial intervention and cardiovascular disease in patients withtype 2 diabetes. N Engl J Med 2003;348:383–393.

373. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M,Moules IK et al. Secondary prevention of macrovascular events inpatients with type 2 diabetes in the PROactive Study (PROspectivepioglitAzone Clinical Trial In macroVascular Events): a randomisedcontrolled trial. Lancet 2005;366:1279–1289.

374. Lewin B, Cay E, Todd I, Goodfield N, Bloomfield P, Elton R. The anginamanagement programme: a rehabiliatation treatment. Br J Cardiol1995;2:221–226.

375. Lewin RJ, Furze G, Robinson J, Griffith K, Wiseman S, Pye M et al. A ran-domised controlled trial of a self-management plan for patients withnewly diagnosed angina. Br J Gen Pract 2002;52:194–6–199–201.

376. Fox KM, Thadani U, Ma PT, Nash SD, Keating Z, Czorniak MA et al.Sildenafil citrate does not reduce exercise tolerance in men with erec-tile dysfunction and chronic stable angina. Eur Heart J 2003;24:2206–2212.

377. Kerins DM. Drugs used for the treatment of myocardial ischaemia.Goodman & Gilmans The Pharmacological Basis of Therapeutics.10th ed. McGraw-Hill; 2001.

378. Mittleman MA, Glasser DB, Orazem J. Clinical trials of sildenafil citrate(Viagra) demonstrate no increase in risk of myocardial infarction andcardiovascular death compared with placebo. Int J Clin Pract2003;57:597–600.

379. Gibbons RJ, Abrams J, Chatterjee K, Daley J, Deedwania PC, Douglas JSet al. ACC/AHA 2002 guideline update for the management of patientswith chronic stable angina–summary article: a report of the AmericanCollege of Cardiology/American Heart Association Task Force on prac-tice guidelines (Committee on the Management of Patients WithChronic Stable Angina). J Am Coll Cardiol 2003;41:159–168.

380. Luscher TF. Treatment of stable angina. Use drugs before percutaneoustransluminal coronary angioplasty. BMJ 2000;321:62–63.

381. Katritsis DG, Ioannidis JP. Percutaneous coronary intervention versusconservative therapy in nonacute coronary artery disease: ameta-analysis. Circulation 2005;111:2906–2912.

382. Hueb W, Soares PR, Gersh BJ, Cesar LA, Luz PL, Puig LB et al. The medi-cine, angioplasty, or surgery study (MASS-II): a randomized, controlledclinical trial of three therapeutic strategies for multivessel coronaryartery disease: 1 year results. J Am Coll Cardiol 2004;43:1743–1751.

383. Antiplatelet Trialists’ Collaboration. Collaborative overview of random-ised trials of antiplatelet therapy–I: Prevention of death, myocardialinfarction, and stroke by prolonged antiplatelet therapy in variouscategories of patients. BMJ 1994;308:81–106.

384. Patrono C, Bachmann F, Baigent C, Bode C, De Caterina R, Charbonnier Bet al. Expert consensus document on the use of antiplatelet agents. Thetask force on the use of antiplatelet agents in patients with athero-sclerotic cardiovascular disease of the European society of cardiology.Eur Heart J 2004;25:166–181.

385. Patrono C, Coller B, FitzGerald GA, Hirsh J, Roth G. Platelet-activedrugs: the relationships among dose, effectiveness, and side effects:the Seventh ACCP Conference on Antithrombotic and ThrombolyticTherapy. Chest 2004;126(Suppl. 3):234S–264S.

386. Patrono C. Aspirin resistance: definition, mechanisms and clinical read-outs. J Thromb Haemost 2003;1:1710–1713.

387. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis ofrandomised trials of antiplatelet therapy for prevention of death, myo-cardial infarction, and stroke in high risk patients. BMJ 2002;324:71–86.

388. Peters RJ, Mehta SR, Fox KA, Zhao F, Lewis BS, Kopecky SL et al. Effectsof aspirin dose when used alone or in combination with clopidogrel inpatients with acute coronary syndromes: observations from theClopidogrel in Unstable angina to prevent Recurrent Events (CURE)study. Circulation 2003;108:1682–1687.

389. Weil J, Colin-Jones D, Langman M, Lawson D, Logan R, Murphy M et al.Prophylactic aspirin and risk of peptic ulcer bleeding. BMJ1995;310:827–830.

390. Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long termuse of aspirin: meta-analysis. BMJ 2000;321:1183–1187.

391. Sudlow C, Baigent C. The adverse effects of different doses of aspirin:a systematic review of randomised trials and observational studies.(Abstract). Stroke 2000;31:2869.

392. Ridker PM, Manson JE, Gaziano JM, Buring JE, Hennekens CH. Low-doseaspirin therapy for chronic stable angina. A randomized, placebo-controlled clinical trial. Ann Intern Med 1991;114:835–839.

393. Fitzgerald GA. Coxibs and cardiovascular disease. N Engl J Med2004;351:1709–1711.

394. Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan Ket al. Cardiovascular events associated with rofecoxib in a colorectaladenoma chemoprevention trial. N Engl J Med 2005;352:1092–1102.

395. Juni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M. Risk ofcardiovascular events and rofecoxib: cumulative meta-analysis. Lancet2004;364:2021–2029.

396. Antman EM, DeMets D, Loscalzo J. Cyclooxygenase inhibition and cardio-vascular risk. Circulation 2005;112:759–770.

397. Solomon SD, McMurray JJ, Pfeffer MA, Wittes J, Fowler R, Finn P et al.Cardiovascular risk associated with celecoxib in a clinical trial for color-ectal adenoma prevention. N Engl J Med 2005;352:1071–1080.

398. Nussmeier NA, Whelton AA, Brown MT, Langford RM, Hoeft A, Parlow JLet al. Complications of the COX-2 inhibitors parecoxib and valdecoxibafter cardiac surgery. N Engl J Med 2005;352:1081–1091.

399. Bennett JS, Daugherty A, Herrington D, Greenland P, Roberts H, Taubert KA.The use of nonsteroidal anti-inflammatory drugs (NSAIDs): a scienceadvisory from the American Heart Association. Circulation 2005;111:1713–1716.

400. Drvota V, Vesterqvist O, Green K. Effects of non-steroidal anti-inflammatory drugs on the in vivo synthesis of thromboxane and prosta-cyclin in humans. Adv Prostaglandin Thromb Leukot Res1991;21A:153–156.

401. Cheng JC, Siegel LB, Katari B, Traynoff SA, Ro JO. Nonsteroidal anti-inflammatory drugs and aspirin: a comparison of the antiplateleteffects. Am J Ther 1997;4:62–65.

402. Capone ML, Tacconelli S, Sciulli MG, Grana M, Ricciotti E, Minuz P et al.Clinical pharmacology of platelet, monocyte, and vascular cyclooxygen-ase inhibition by naproxen and low-dose aspirin in healthy subjects.Circulation 2004;109:1468–1471.

403. Reilly IA, FitzGerald GA. Inhibition of thromboxane formation in vivoand ex vivo: implications for therapy with platelet inhibitory drugs.Blood 1987;69:180–186.

404. Kimmel SE, Berlin JA, Reilly M, Jaskowiak J, Kishel L, Chittams J et al.The effects of nonselective non-aspirin non-steroidal anti-inflammatorymedications on the risk of nonfatal myocardial infarction and theirinteraction with aspirin. J Am Coll Cardiol 2004;43:985–990.

405. Garcia Rodriguez LA, Varas-Lorenzo C, Maguire A, Gonzalez-Perez A. -Nonsteroidal antiinflammatory drugs and the risk of myocardial infarc-tion in the general population. Circulation 2004;109:3000–3006.

406. Solomon DH, Glynn RJ, Levin R, Avorn J. Nonsteroidal anti-inflammatorydrug use and acute myocardial infarction. Arch Intern Med2002;162:1099–1104.

407. Baigent C, Patrono C. Selective cyclooxygenase 2 inhibitors, aspirin, andcardiovascular disease: a reappraisal. Arthritis Rheum 2003;48:12–20.

408. www.fda.gov.medwatch/safety (2005)409. Rao GH, Johnson GG, Reddy KR, White JG. Ibuprofen protects platelet

cyclooxygenase from irreversible inhibition by aspirin. Arteriosclerosis1983;3:383–388.

410. Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara AJ, DeMarco S,Tournier B et al. Cyclooxygenase inhibitors and the antiplateleteffects of aspirin. N Engl J Med 2001;345:1809–1817.

411. Cronberg S, Wallmark E, Soderberg I. Effect on platelet aggregation oforal administration of 10 non-steroidal analgesics to humans. Scand JHaematol 1984;33:155–159.

412. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrelversus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet1996;348:1329–1339.

413. Kapetanakis EI, Medlam DA, Boyce SW, Haile E, Hill PC, Dullum MK et al.Clopidogrel administration prior to coronary artery bypass graftingsurgery: the cardiologist’s panacea or the surgeon’s headache? EurHeart J 2005;26:576–583.

414. Lau WC, Waskell LA, Watkins PB, Neer CJ, Horowitz K, Hopp AS et al.Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggre-gation: a new drug-drug interaction. Circulation 2003;107:32–37.

415. Mitsios JV, Papathanasiou AI, Rodis FI, Elisaf M, Goudevenos JA, TselepisAD. Atorvastatin does not affect the antiplatelet potency of clopidogrel

56 ESC Guidelines

when it is administered concomitantly for 5 weeks in patients withacute coronary syndromes. Circulation 2004;109:1335–1338.

416. Neubauer H, Gunesdogan B, Hanefeld C, Spiecker M, Mugge A. Lipophilicstatins interfere with the inhibitory effects of clopidogrel on plateletfunction–a flow cytometry study. Eur Heart J 2003;24:1744–1749.

417. Serebruany VL, Midei MG, Malinin AI, Oshrine BR, Lowry DR, Sane DCet al. Absence of interaction between atorvastatin or other statinsand clopidogrel: results from the interaction study. Arch Intern Med2004;164:2051–2057.

418. Muller I, Besta F, Schulz C, Li Z, Massberg S, Gawaz M. Effects of statinson platelet inhibition by a high loading dose of clopidogrel. Circulation2003;108:2195–2197.

419. Gorchakova O, von Beckerath N, Gawaz M, Mocz A, Joost A, Schomig Aet al. Antiplatelet effects of a 600 mg loading dose of clopidogrel arenot attenuated in patients receiving atorvastatin or simvastatin for atleast 4 weeks prior to coronary artery stenting. Eur Heart J2004;25:1898–1902.

420. Lim MJ, Spencer FA, Gore JM, Dabbous OH, Agnelli G, Kline-Rogers EMet al. Impact of combined pharmacologic treatment with clopidogreland a statin on outcomes of patients with non-ST-segment elevationacute coronary syndromes: perspectives from a large multinationalregistry. Eur Heart J 2005;26:1063–1069.

421. Cryer B. Reducing the risks of gastrointestinal bleeding with antiplatelettherapies. N Engl J Med 2005;352:287–289.

422. Chan FK. Helicobacter pylori and nonsteroidal anti-inflammatory drugs.Gastroenterol Clin North Am 2001;30:937–952.

423. Lai KC, Lam SK, Chu KM, Wong BC, Hui WM, Hu WH et al. Lansoprazolefor the prevention of recurrences of ulcer complications from long-termlow-dose aspirin use. N Engl J Med 2002;346:2033–2038.

424. Chan FK, Ching JY, Hung LC, Wong VW, Leung VK, Kung NN et al.Clopidogrel versus aspirin and esomeprazole to prevent recurrentulcer bleeding. N Engl J Med 2005;352:238–244.

425. Kaufmann PA, Mandinov L, Seiler C, Hess OM. Impact ofexercise-induced coronary vasomotion on anti-ischaemic therapy.Coron Artery Dis 2000;11:363–369.

426. McKee SA, Sane DC, Deliargyris EN. Aspirin resistance in cardiovasculardisease: a review of prevalence, mechanisms, and clinical significance.Thromb Haemost 2002;88:711–715.

427. Michelson AD, Cattaneo M, Eikelboom JW, Gurbel P, Kottke-Marchant K,Kunicki TJ et al. Aspirin resistance: position paper of the Working Groupon Aspirin Resistance. J Thromb Haemost 2005;3:1309–1311.

428. Wiviott SD, Antman EM. Clopidogrel resistance: a new chapter in afast-moving story. Circulation 2004;109:3064–3067.

429. Cattaneo M. Aspirin and clopidogrel: efficacy, safety, and the issue ofdrug resistance. Arterioscler Thromb Vasc Biol 2004;24:1980–1987.

430. Nguyen TA, Diodati JG, Pharand C. Resistance to clopidogrel: a review ofthe evidence. J Am Coll Cardiol 2005;45:1157–1164.

431. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DBet al. Implications of recent clinical trials for the National CholesterolEducation Program Adult Treatment Panel III Guidelines. J Am CollCardiol 2004;44:720–732.

432. The Scandinavian Simvastatin Survival Study (4S). Randomised trial ofcholesterol lowering in 4444 patients with coronary heart disease.Lancet 1994;344:1383–1389.

433. Sacks FM, Tonkin AM, Shepherd J, Braunwald E, Cobbe S, Hawkins CMet al. Effect of pravastatin on coronary disease events in subgroupsdefined by coronary risk factors: the Prospective Pravastatin PoolingProject. Circulation 2000;102:1893–1900.

434. The Long-Term Intervention with Pravastatin in Ischaemic Disease(LIPID) Study Group. Prevention of cardiovascular events and deathwith pravastatin in patients with coronary heart disease and a broadrange of initial cholesterol levels. N Engl J Med 1998;339:1349–1357.

435. Heart Protection Study Collaborative Group. MRC/BHF Heart ProtectionStudy of cholesterol lowering with simvastatin in 20,536 high-riskindividuals: a randomised placebo-controlled trial. Lancet 2002;360(9326):7–22.

436. Goldberg RB, Mellies MJ, Sacks FM, Moye LA, Howard BV, Howard WJet al. Cardiovascular events and their reduction with pravastatin in dia-betic and glucose-intolerant myocardial infarction survivors withaverage cholesterol levels: subgroup analyses in the cholesterol andrecurrent events (CARE) trial. The Care Investigators. Circulation1998;98:2513–2519.

437. Collins R, Armitage J, Parish S, Sleigh P, Peto R. MRC/BHF HeartProtection Study of cholesterol-lowering with simvastatin in 5963people with diabetes: a randomised placebo-controlled trial. Lancet2003;361:2005–2016.

438. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SMet al. Pravastatin in elderly individuals at risk of vascular disease(PROSPER): a randomised controlled trial. Lancet 2002;360:1623–1630.

439. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA,Livingstone SJ et al. Primary prevention of cardiovascular disease withatorvastatin in type 2 diabetes in the Collaborative AtorvastatinDiabetes Study (CARDS): multicentre randomised placebo-controlledtrial. Lancet 2004;364:685–696.

440. Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M et al.Prevention of coronary and stroke events with atorvastatin in hyperten-sive patients who have average or lower-than-average cholesterol con-centrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–LipidLowering Arm (ASCOT-LLA): a multicentre randomised controlled trial.Lancet 2003;361:1149–1158.

441. Faggiotto A, Paoletti R. State-of-the-Art lecture. Statins and blockers ofthe renin-angiotensin system: vascular protection beyond their primarymode of action. Hypertension 1999;34:987–996.

442. Bonetti PO, Lerman LO, Napoli C, Lerman A. Statin effects beyond lipidlowering–are they clinically relevant? Eur Heart J 2003;24:225–248.

443. Rosenson RS, Tangney CC. Antiatherothrombotic properties of statins:implications for cardiovascular event reduction. JAMA 1998;279:1643–1650.

444. Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM, McCabe CH et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med2005;352:20–28.

445. Pasceri V, Patti G, Nusca A, Pristipino C, Richichi G, Di Sciascio G.Randomized trial of atorvastatin for reduction of myocardial damageduring coronary intervention: results from the ARMYDA (Atorvastatinfor Reduction of MYocardial Damage during Angioplasty) study.Circulation 2004;110:674–678.

446. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C et al.Efficacy and safety of cholesterol-lowering treatment: prospectivemeta-analysis of data from 90,056 participants in 14 randomised trialsof statins. Lancet 2005;366:1267–1278.

447. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC et al.Intensive lipid lowering with atorvastatin in patients with stable coro-nary disease. N Engl J Med 2005;352:1425–1435.

448. Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ,Holme I et al. High-dose atorvastatin versus usual-dose simvastatin forsecondary prevention after myocardial infarction: the IDEAL study: arandomized controlled trial. JAMA 2005;294:2437–2445.

449. Wierzbicki AS. Ezetimibe: a new addition to lipid-lowering therapy. Int JClin Pract 2003;57:653–655.

450. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB et al.Gemfibrozil for the secondary prevention of coronary heart disease inmen with low levels of high-density lipoprotein cholesterol. VeteransAffairs High-Density Lipoprotein Cholesterol Intervention Trial StudyGroup. N Engl J Med 1999;341:410–418.

451. Farnier M. Combination therapy with an HMG-CoA reductase inhibitorand a fibric acid derivative: a critical review of potential benefits anddrawbacks. Am J Cardiovasc Drugs 2003;3:169–178.

452. Robins SJ, Rubins HB, Faas FH, Schaefer EJ, Elam MB, Anderson JW et al.Insulin resistance and cardiovascular events with low HDL cholesterol:the Veterans Affairs HDL Intervention Trial (VA-HIT). Diabetes Care2003;26:1513–1517.

453. Prueksaritanont T, Tang C, Qiu Y, Mu L, Subramanian R, Lin JH. Effects offibrates on metabolism of statins in human hepatocytes. Drug MetabDispos 2002;30:1280–1287.

454. Pan WJ, Gustavson LE, Achari R, Rieser MJ, Ye X, Gutterman C et al.Lack of a clinically significant pharmacokinetic interaction betweenfenofibrate and pravastatin in healthy volunteers. J Clin Pharmacol2000;40:316–323.

455. Keech A, Simes RJ, Barter P, Best J, Scott R, Takinen MR, Foreder P, Pillai A,Davis T, Glasziou P, Drury P, Kesaniemi YA, Sullivan D, Hunt, Colman D,d’Emden P, M.Whiting M, Ehnholm C, Laakso M, FIELD study investigators.Effects of long-term ffenofibrate therapy on cardiovascular events in 9795people with type 2 diabetes mellitus (the FIELD study): randomised con-trolled trial. Lancet 2005;366:1829–1831.

456. Brousseau ME, Schaefer EJ, Wolfe ML, Blodon LT, Digenio AG, Clark RW,Manuscu JP, Rader DJ. Effects of an inhibitor of cholesteryl ester trans-fer protein on HDL cholesterol. N Engl J Med 2004;350:1491–1494.

457. Turnbull F. Effects of different blood-pressure-lowering regimens onmajor cardiovascular events: results of prospectively-designed over-views of randomised trials. Lancet 2003;362:1527–1535.

ESC Guidelines 57

458. Staessen JA, Wang JG, Thijs L. Cardiovascular prevention and bloodpressure reduction: a quantitative overview updated until 1 March2003. J Hypertens 2003;21:1055–1076.

459. Psaty BM, Lumley T, Furberg CD, Schellenbaum G, Pahor M, Alderman MHet al. Health outcomes associated with various antihypertensivetherapies used as first-line agents: a network meta-analysis. JAMA2003;289:2534–2544.

460. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of anangiotensin-converting-enzyme inhibitor, ramipril, on cardiovascularevents in high-risk patients. The Heart Outcomes PreventionEvaluation Study Investigators. N Engl J Med 2000;342:145–153.

461. Fox KM. Efficacy of perindopril in reduction of cardiovascular eventsamong patients with stable coronary artery disease: randomised,double-blind, placebo-controlled, multicentre trial (the EUROPAstudy). Lancet 2003;362:782–788.

462. Gustafsson I T-PC, Kober L, Gustafsson F HP. Effect of the angiotensin-converting enzyme inhibitor trandopril on mortality and morbidity indiabetic patients with left ventricular dysfunction after acute myocar-dial infarction. Trace Study Group. 1999;34:83–89.

463. Luft FC. Recent clinical trial highlights in hypertension. Curr HypertensRep 2001;3:133–138.

464. Svensson P, de Faire U, Sleight P, Yusuf S, Ostergren J. Comparativeeffects of ramipril on ambulatory and office blood pressures: a HOPESubstudy. Hypertension 2001;38:E28–E32.

465. Daly CA, Fox KM, Remme WJ, Bertrand ME, Ferrari R, Simoons ML. Theeffect of perindopril on cardiovascular morbidity and mortality inpatients with diabetes in the EUROPA study: results from the PERSUADEsubstudy. Eur Heart J 2005;26:1369–1378.

466. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific rel-evance of usual blood pressure to vascular mortality: a meta-analysisof individual data for one million adults in 61 prospective studies.Lancet 2002;360:1903–1913.

467. Nissen SE, Tuzcu EM, Libby P, Thompson PD, Ghali M, Garza D et al.Effect of antihypertensive agents on cardiovascular events in patientswith coronary disease and normal blood pressure: the CAMELOT study:a randomized controlled trial. JAMA 2004;292:2217–2225.

468. Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L et al.Outcomes in hypertensive patients at high cardiovascular risk treatedwith regimens based on valsartan or amlodipine: the VALUE randomisedtrial. Lancet 2004;363:2022–2031.

469. Poulter NR, Wedel H, Dahlof B, Sever PS, Beevers DG, Caulfield M et al.Role of blood pressure and other variables in the differential cardio-vascular event rates noted in the Anglo-Scandinavian CardiacOutcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA). Lancet2005;366:907–913.

470. Staessen J, Birkenhager WH. Evidence that new antihypertensives aresuperior to older drugs. Lancet 2005;366:869–871.

471. Jackson R, Lawes CM, Bennett DA, Milne RJ, Rodgers A. Treatment withdrugs to lower blood pressure and blood cholesterol based on an individ-ual’s absolute cardiovascular risk. Lancet 2005;365:434–441.

472. Lonn EM, Yusuf S, Jha P, Montague TJ, Teo KK, Benedict CR et al.Emerging role of angiotensin-converting enzyme inhibitors in cardiacand vascular protection. Circulation 1994;90:2056–2069.

473. Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Kober L, Maggioni APet al. Valsartan, captopril, or both in myocardial infarction complicatedby heart failure, left ventricular dysfunction, or both. N Engl J Med2003;349:1893–1906.

474. Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ et al.Effects of candesartan in patients with chronic heart failure and pre-served left-ventricular ejection fraction: the CHARM-Preserved Trial.Lancet 2003;362:777–781.

475. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B et al.Randomized trial of estrogen plus progestin for secondary preventionof coronary heart disease in postmenopausal women. Heart andEstrogen/progestin Replacement Study (HERS) Research Group. JAMA1998;280:605–613.

476. Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky Met al. Cardiovascular disease outcomes during 6.8 years of hormonetherapy: Heart and Estrogen/progestin Replacement Study follow-up(HERS II). JAMA 2002;288:49–57.

477. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C,Stefanick ML et al. Risks and benefits of estrogen plus progestin inhealthy postmenopausal women: principal results From the Women’sHealth Initiative randomized controlled trial. JAMA 2002;288:321–333.

478. Manson JE, Hsia J, Johnson KC, Rossouw JE, Assaf AR, Lasser NL et al.Estrogen plus progestin and the risk of coronary heart disease. N EnglJ Med 2003;349:523–534.

479. Hersh AL, Stefanick ML, Stafford RS. National use of postmenopausalhormone therapy: annual trends and response to recent evidence.JAMA 2004;291:47–53.

480. Yusuf S, Wittes J, Friedman L. Overview of results of randomized clinicaltrials in heart disease. I. Treatments following myocardial infarction.JAMA 1988;260:2088–2093.

481. Freemantle N, Urdahl H, Eastaugh J, Hobbs FD. What is the place ofbeta-blockade in patients who have experienced a myocardial infarctionwith preserved left ventricular function? Evidence and (mis)interpreta-tion. Prog Cardiovasc Dis 2002;44:243–250.

482. Carlberg B, Samuelsson O, Lindholm LH. Atenolol in hypertension: is it awise choice? Lancet 2004;364:1684–1689.

483. Hjemdahl P, Eriksson SV, Held C, Forslund L, Nasman P, Rehnqvist N.Favourable long term prognosis in stable angina pectoris: an extendedfollow up of the angina prognosis study in Stockholm (APSIS). Heart2006;92(2):177–182. [EPub ahead of print June 10, 2005]

484. Pepine CJ, Cohn PF, Deedwania PC, Gibson RS, Handberg E, Hill JA et al.Effects of treatment on outcome in mildly symptomatic patients withischemia during daily life. The Atenolol Silent Ischemia Study (ASIST).Circulation 1994;90:762–768.

485. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XLRandomised Intervention Trial in Congestive Heart Failure (MERIT-HF).Lancet 1999;353:2001–2007.

486. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomisedtrial. Lancet 1999;353:9–13.

487. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM et al.The effect of carvedilol on morbidity and mortality in patients withchronic heart failure. U.S. Carvedilol Heart Failure Study Group.N 0Engl J Med 1996;334:1349–1355.

488. Effect of verapamil on mortality and major events after acute myocar-dial infarction (the Danish Verapamil Infarction Trial II–DAVIT II). Am JCardiol 1990;66:779–785.

489. The Multicenter Diltiazem Postinfarction Trial Research Group. Theeffect of diltiazem on mortality and reinfarction after myocardialinfarction. N Engl J Med 1988;319:385–392.

490. Boden WE, van Gilst WH, Scheldewaert RG, Starkey IR, Carlier MF, JulianDG et al. Diltiazem in acute myocardial infarction treated with throm-bolytic agents: a randomised placebo-controlled trial. IncompleteInfarction Trial of European Research Collaborators EvaluatingPrognosis post-Thrombolysis (INTERCEPT). Lancet 2000;355:1751–1756.

491. Furberg CD, Psaty BM, Meyer JV. Nifedipine. Dose-related increase inmortality in patients with coronary heart disease. Circulation1995;92:1326–1331.

492. Stason WB, Schmid CH, Niedzwiecki D, Whiting GW, Caubet JF, Cory Det al. Safety of nifedipine in angina pectoris: a meta-analysis.Hypertension 1999;33:24–31.

493. Poole-Wilson PA, Lubsen J, Kirwan BA, van Dalen FJ, Wagener G,Danchin N et al. Effect of long-acting nifedipine on mortality and cardio-vascular morbidity in patients with stable angina requiring treatment(ACTION trial): randomised controlled trial. Lancet 2004;364:849–857.

494. Heidenreich PA, McDonald KM, Hastie T, Fadel B, Hagan V, Lee BK et al.Meta-analysis of trials comparing beta-blockers, calcium antagonists,and nitrates for stable angina. JAMA 1999;281:1927–1936.

495. Parker JD, Parker JO. Nitrate therapy for stable angina pectoris. N EnglJ Med 1998;338:520–531.

496. Thadani U, Lipicky RJ. Short and long-acting oral nitrates for stableangina pectoris. Cardiovasc Drugs Ther 1994;8:611–623.

497. ISIS-4 (Fourth International Study of Infarct Survival) CollaborativeGroup. ISIS-4: a randomised factorial trial assessing early oral captopril,oral mononitrate, and intravenous magnesium sulphate in 58,050patients with suspected acute myocardial infarction. Lancet1995;345:669–685.

498. Gruppo Italiano per lo Studio della Sopravvivenza nell’infartoMiocardico. GISSI-3: effects of lisinopril and transdermal glyceryl trini-trate singly and together on 6-week mortality and ventricular functionafter acute myocardial infarction. Lancet 1994;343:1115–1122.

499. Thadani U, Lipicky RJ. Ointments and transdermal nitroglycerin patchesfor stable angina pectoris. Cardiovasc Drugs Ther 1994;8:625–633.

500. Parker JD, Parker AB, Farrell B, Parker JO. Intermittent transdermalnitroglycerin therapy. Decreased anginal threshold during the nitrate-free interval. Circulation 1995;91:973–978.

501. Pepine CJ, Lopez LM, Bell DM, Handberg-Thurmond EM, Marks RG,McGorray S. Effects of intermittent transdermal nitroglycerin on

58 ESC Guidelines

occurrence of ischemia after patch removal: results of the second trans-dermal intermittent dosing evaluation study (TIDES-II). J Am CollCardiol 1997;30:955–961.

502. Savonitto S, Ardissino D. Selection of drug therapy in stable anginapectoris. Cardiovasc Drugs Ther 1998;12:197–210.

503. Thadani U. Treatment of stable angina. Curr Opin Cardiol1999;14:349–358.

504. Ko DT, Hebert PR, Coffey CS, Sedrakyan A, Curtis JP, Krumholz HM.Beta-blocker therapy and symptoms of depression, fatigue, and sexualdysfunction. JAMA 2002;288:351–357.

505. Hjemdahl P, Wiklund IK. Quality of life on antihypertensive drugtherapy: scientific end-point or marketing exercise? J Hypertens1992;10:1437–1446.

506. Neaton JD, Grimm RH Jr, Prineas RJ, Stamler J, Grandits GA, Elmer PJet al. Treatment of Mild Hypertension Study. Final results. Treatmentof Mild Hypertension Study Research Group. JAMA 1993;270:713–724.

507. Hjemdahl P, Wallen NH. Calcium antagonist treatment, sympatheticactivity and platelet function. Eur Heart J 1997;18(Suppl. A):A36–A50.

508. Karlson BW, Emanuelsson H, Herlitz J, Nilsson JE, Olsson G. Evaluationof the antianginal effect of nifedipine: influence of formulation depen-dent pharmacokinetics. Eur J Clin Pharmacol 1991;40:501–506.

509. Waters D. Proischemic complications of dihydropyridine calcium channelblockers. Circulation 1991;84:2598–2600.

510. Deanfield JE, Detry JM, Lichtlen PR, Magnani B, Sellier P, Thaulow E.Amlodipine reduces transient myocardial ischemia in patients withcoronary artery disease: double-blind Circadian Anti-Ischemia Programin Europe (CAPE Trial). J Am Coll Cardiol 1994;24:1460–1467.

511. Packer M, O’Connor CM, Ghali JK, Pressler ML, Carson PE, Belkin RNet al. Effect of amlodipine on morbidity and mortality in severechronic heart failure. Prospective Randomized Amlodipine SurvivalEvaluation Study Group. N Engl J Med 1996;335:1107–1114.

512. Ardissino D, Savonitto S, Egstrup K, Rasmussen K, Bae EA, Omland Tet al. Selection of medical treatment in stable angina pectoris:results of the International Multicenter Angina Exercise (IMAGE) Study.J Am Coll Cardiol 1995;25:1516–1521.

513. Forslund L, Hjemdahl P, Held C, Bjorkander I, Eriksson SV, Brodin U et al.Prognostic implications of results from exercise testing in patients withchronic stable angina pectoris treated with metoprolol or verapamil. Areport from the Angina Prognosis Study In Stockholm (APSIS). Eur Heart J2000;21:901–910.

514. Arnim TV. Medical treatment to reduce total ischaemic burden: totalischaemic burden bisoprolol study (TIBBS), a multicenter trial compar-ing bisoprolol and nifedipine. The TIBBS Investigators. J Am CollCardiol 1995;25:231–238.

515. Fox KM, Mulcahy D, Findlay I, Ford I, Dargie HJ. The Total IschaemicBurden European Trial (TIBET). Effects of atenolol, nifedipine SR andtheir combination on the exercise test and the total ischaemic burdenin 608 patients with stable angina. The TIBET Study Group. Eur HeartJ 1996;17:96–103.

516. Markham A, Plosker GL, Goa KL. Nicorandil. An updated review of its usein ischaemic heart disease with emphasis on its cardioprotectiveeffects. Drugs 2000;60:955–974.

517. Rajaratnam R, Brieger DB, Hawkins R, Freedman SB. Attenuation ofanti-ischaemic efficacy during chronic therapy with nicorandil inpatients with stable angina pectoris. Am J Cardiol 1999;83:1120–1124, A9.

518. Nicorandil for angina–an update. Drug Ther Bull. 2003;41:86–88.519. Borer JS, Fox K, Jaillon P, Lerebours G. Antianginal and antiischemic

effects of ivabradine, an I(f) inhibitor, in stable angina: a randomized,double-blind, multicentered, placebo-controlled trial. Circulation2003;107:817–823.

520. Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K. Efficacy of ivabradine,a new selective If inhibitor, compared with atenolol in patients withchronic stable angina. Eur Heart J 2005;26:2529–2536.

521. Antzelevitch C, Belardinelli L, Zygmunt AC, Burashnikov A, Di Diego JM,Fish JM et al. Electrophysiological effects of ranolazine, a novel anti-anginal agent with antiarrhythmic properties. Circulation 2004;110:904–910.

522. Haigney MC, Lakatta EG, Stern MD, Silverman HS. Sodium channel block-ade reduces hypoxic sodium loading and sodium-dependent calciumloading. Circulation 1994;90:391–399.

523. Ver Donck L, Borgers M, Verdonck F. Inhibition of sodium and calciumoverload pathology in the myocardium: a new cytoprotective principle.Cardiovasc Res 1993;27:349–357.

524. Marzilli M, Klein WW. Efficacy and tolerability of trimetazidine in stableangina: a meta-analysis of randomized, double-blind, controlled trials.Coron Artery Dis 2003;14:171–179.

525. Cross HR. Trimetazidine for stable angina pectoris. Expert OpinPharmacother 2001;2:857–875.

526. Chazov EI, Lepakchin VK, Zharova EA, Fitilev SB, Levin AM, RumiantzevaEG et al. Trimetazidine in Angina Combination Therapy–the TACT study:trimetazidine versus conventional treatment in patients with stableangina pectoris in a randomized, placebo-controlled, multicenterstudy. Am J Ther 2005;12:35–42.

527. Chaitman BR, Skettino SL, Parker JO, Hanley P, Meluzin J, Kuch J et al.Anti-ischaemic effects and long-term survival during ranolazine mono-therapy in patients with chronic severe angina. J Am Coll Cardiol2004;43:1375–1382.

528. Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch Jet al. Effects of ranolazine with atenolol, amlodipine, or diltiazem onexercise tolerance and angina frequency in patients with severechronic angina: a randomized controlled trial. JAMA 2004;291:309–316.

529. Messin R, Opolski G, Fenyvesi T, Carreer-Bruhwyler F, Dubois C,Famaey JP et al. Efficacy and safety of molsidomine once-a-day inpatients with stable angina pectoris. Int J Cardiol 2005;98:79–89.

530. Tolins M, Weir EK, Chesler E, Pierpont GL. ‘Maximal’ drug therapy is notnecessarily optimal in chronic angina pectoris. J Am Coll Cardiol1984;3:1051–1057.

531. Jackson G. Stable angina: maximal medical therapy is not the same asoptimal medical therapy. Int J Clin Pract 2000;54:351.

532. Kaski JC, Valenzuela Garcia LF. Therapeutic options for the managementof patients with cardiac syndrome X. Eur Heart J 2001;22:283–293.

533. Cannon RO III, Watson RM, Rosing DR, Epstein SE. Efficacy of calciumchannel blocker therapy for angina pectoris resulting from small-vesselcoronary artery disease and abnormal vasodilator reserve. Am J Cardiol1985;56:242–246.

534. Lanza GA, Colonna G, Pasceri V, Maseri A. Atenolol versus amlodipineversus isosorbide-5-mononitrate on anginal symptoms in syndrome X.Am J Cardiol 1999;84:854–856. A8.

535. Camici PG, Marraccini P, Gistri R, Salvadori PA, Sorace O, L’Abbate A.Adrenergically mediated coronary vasoconstriction in patients withsyndrome X. Cardiovasc Drugs Ther 1994;8:221–226.

536. Botker HE, Sonne HS, Schmitz O, Nielsen TT. Effects of doxazosin onexercise-induced angina pectoris, ST-segment depression, and insulinsensitivity in patients with syndrome X. Am J Cardiol1998;82:1352–1356.

537. Galassi AR, Kaski JC, Pupita G, Vejar M, Crea F, Maseri A. Lack ofevidence for alpha-adrenergic receptor-mediated mechanisms in thegenesis of ischemia in syndrome X. Am J Cardiol 1989;64:264–269.

538. Yamabe H, Namura H, Yano T, Fujita H, Kim S, Iwahashi M et al. Effect ofnicorandil on abnormal coronary flow reserve assessed by exercise 201Tlscintigraphy in patients with angina pectoris and nearly normal coronaryarteriograms. Cardiovasc Drugs Ther 1995;9:755–761.

539. Rogacka D, Guzik P, Wykretowicz A, Rzezniczak J, Dziarmaga M, Wysocki H.Effects of trimetazidine on clinical symptoms and tolerance of exercise ofpatients with syndrome X: a preliminary study. Coron Artery Dis2000;11:171–177.

540. Ozcelik F, Altun A, Ozbay G. Antianginal and anti-ischaemic effects ofnisoldipine and ramipril in patients with syndrome X. Clin Cardiol1999;22:361–365.

541. Kayikcioglu M, Payzin S, Yavuzgil O, Kultursay H, Can LH, Soydan I.Benefits of statin treatment in cardiac syndrome-X1. Eur Heart J2003;24:1999–2005.

542. Pizzi C, Manfrini O, Fontana F, Bugiardini R. Angiotensin-convertingenzyme inhibitors and 3-hydroxy-3-methylglutaryl coenzyme areductase in cardiac Syndrome X: role of superoxide dismutase activity.Circulation 2004;109:53–58.

543. Kaski JC, Rosano G, Gavrielides S, Chen L. Effects of angiotensin-converting enzyme inhibition on exercise-induced angina and STsegment depression in patients with microvascular angina. J Am CollCardiol 1994;23:652–657.

544. Nalbantgil I, Onder R, Altintig A, Nalbantgil S, Kiliccioglu B, Boydak Bet al. Therapeutic benefits of cilazapril in patients with syndrome X. -Cardiology 1998;89:130–133.

545. Kaski JC. Pathophysiology and management of patients with chest painand normal coronary arteriograms (cardiac syndrome X). Circulation2004;109:568–572.

546. Cannon RO III, Quyyumi AA, Mincemoyer R, Stine AM, Gracely RH,Smith WB et al. Imipramine in patients with chest pain despite normalcoronary angiograms. N Engl J Med 1994;330:1411–1417.

ESC Guidelines 59

547. Yoshio H, Shimizu M, Kita Y, Ino H, Kaku B, Taki J et al. Effects of short-term aminophylline administration on cardiac functional reserve inpatients with syndrome X. J Am Coll Cardiol 1995;25:1547–1551.

548. Lanza GA, Sestito A, Sgueglia GA, Infusino F, Papacci F, Visocchi M et al.Effect of spinal cord stimulation on spontaneous and stress-inducedangina and ‘ischemia-like’ ST-segment depression in patients withcardiac syndrome X. Eur Heart J 2005;

549. Eriksson BE, Tyni-Lenne R, Svedenhag J, Hallin R, Jensen-Urstad K,Jensen-Urstad M et al. Physical training in Syndrome X: physicaltraining counteracts deconditioning and pain in Syndrome X. J AmColl Cardiol 2000;36:1619–1625.

550. Sitges M, Heras M, Roig E, Duran M, Masotti M, Zurbano MJ et al. Acuteand mid-term combined hormone replacement therapy improves endo-thelial function in post-menopausal women with angina and angiogra-phically normal coronary arteries. Eur Heart J 2001;22:2116–2124.

551. Rosano GM, Peters NS, Lefroy D, Lindsay DC, Sarrel PM, Collins P et al.17-beta-Estradiol therapy lessens angina in postmenopausal womenwith syndrome X. J Am Coll Cardiol 1996;28:1500–1505.

552. Chevalier P, Dacosta A, Defaye P, Chalvidan T, Bonnefoy E, Kirkorian Get al. Arrhythmic cardiac arrest due to isolated coronary arteryspasm: long-term outcome of seven resuscitated patients. J Am CollCardiol 1998;31:57–61.

553. Ricci DR, Orlick AE, Cipriano PR, Guthaner DF, Harrison DC. Alteredadrenergic activity in coronary arterial spasm: insight into mechanismbased on study of coronary hemodynamics and the electrocardiogram.Am J Cardiol 1979;43:1073–1079.

554. Lablanche JM, Bauters C, McFadden EP, Quandalle P, Bertrand ME.Potassium channel activators in vasospastic angina. Eur Heart J1993;14(Suppl. B):22–24.

555. Khatri S, Webb JG, Carere RG, Dodek A. Stenting for coronary arteryspasm. Catheter Cardiovasc Interv 2002;56:16–20.

556. Gaspardone A, Tomai F, Versaci F, Ghini AS, Polisca P, Crea F et al.Coronary artery stent placement in patients with variant angina refrac-tory to medical treatment. Am J Cardiol 1999;84:96–98. A8.

557. Waters DD, Bouchard A, Theroux P. Spontaneous remission is a frequentoutcome of variant angina. J Am Coll Cardiol 1983;2:195–199.

558. Jones RH, Kesler K, Phillips HR III, Mark DB, Smith PK, Nelson CL et al.Long-term survival benefits of coronary artery bypass grafting andpercutaneous transluminal angioplasty in patients with coronaryartery disease. J Thorac Cardiovasc Surg 1996;111:1013–1025.

559. Myocardial infarction and mortality in the coronary artery surgery study(CASS) randomized trial. N Engl J Med 1984;310:750–758.

560. Hoffman SN, TenBrook JA, Wolf MP, Pauker SG, Salem DN, Wong JB. Ameta-analysis of randomized controlled trials comparing coronaryartery bypass graft with percutaneous transluminal coronaryangioplasty: one- to 8 year outcomes. J Am Coll Cardiol 2003;41:1293–1304.

561. Hamm CW, Reimers J, Ischinger T, Rupprecht HJ, Berger J, Bleifeld W. Arandomized study of coronary angioplasty compared with bypass surgeryin patients with symptomatic multivessel coronary disease. GermanAngioplasty Bypass Surgery Investigation (GABI). N Engl J Med1994;331:1037–1043.

562. Rodriguez A, Rodriguez Alemparte M, Baldi J, Navia J, Delacasa A,Vogel D et al. Coronary stenting versus coronary bypass surgery inpatients with multiple vessel disease and significant proximal LADstenosis: results from the ERACI II study. Heart 2003;89:184–188.

563. Goy JJ, Eeckhout E, Moret C, Burnand B, Vogt P, Stauffer JC et al.5 year outcome in patients with isolated proximal left anterior descend-ing coronary artery stenosis treated by angioplasty or left internalmammary artery grafting. A prospective trial. Circulation 1999;99:3255–3259.

564. Nilsson J, Algotsson L, Hoglund P, Luhrs C, Brandt J. Early mortality incoronary bypass surgery: the EuroSCORE versus The Society of ThoracicSurgeons risk algorithm. Ann Thorac Surg 2004;77:1235–1239; discussion1239–1240.

565. Nashef SA, Roques F, Michel P, Gauducheau E, Lemeshow S, Salamon R.European system for cardiac operative risk evaluation (EuroSCORE). EurJ Cardiothorac Surg 1999;16:9–13.

566. Goldman S, Zadina K, Moritz T, Ovitt T, Sethi G, Copeland JG et al. Long-term patency of saphenous vein and left internal mammary artery graftsafter coronary artery bypass surgery: results from a Department ofVeterans Affairs Cooperative Study. J Am Coll Cardiol 2004;44:2149–2156.

567. Lytle BW, Loop FD, Cosgrove DM, Ratliff NB, Easley K, Taylor PC. Long-term (5 to 12 years) serial studies of internal mammary artery and

saphenous vein coronary bypass grafts. J Thorac Cardiovasc Surg1985;89:248–258.

568. Cameron A, Davis KB, Green G, Schaff HV. Coronary bypass surgery withinternal-thoracic-artery grafts–effects on survival over a 15-yearperiod. N Engl J Med 1996;334:216–219.

569. Lytle BW, Blackstone EH, Loop FD, Houghtaling PL, Arnold JH, Akhrass Ret al. Two internal thoracic artery grafts are better than one. J ThoracCardiovasc Surg 1999;117:855–872.

570. Brodman RF, Frame R, Camacho M, Hu E, Chen A, Hollinger I. Routine useof unilateral and bilateral radial arteries for coronary artery bypassgraft surgery. J Am Coll Cardiol 1996;28:959–963.

571. Acar C, Ramsheyi A, Pagny JY, Jebara V, Barrier P, Fabiani JN et al.The radial artery for coronary artery bypass grafting: clinical andangiographic results at 5 years. J Thorac Cardiovasc Surg1998;116:981–989.

572. van Dijk D, Nierich AP, Jansen EW, Nathoe HM, Suyker WJ, Diephuis JCet al. Early outcome after off-pump versus on-pump coronary bypasssurgery: results from a randomized study. Circulation 2001;104:1761–1766.

573. Angelini GD, Taylor FC, Reeves BC, Ascione R. Early and midtermoutcome after off-pump and on-pump surgery in Beating Heart AgainstCardioplegic Arrest Studies (BHACAS 1 and 2): a pooled analysis of tworandomised controlled trials. Lancet 2002;359:1194–1199.

574. Khan NE, De Souza A, Mister R, Flather M, Clague J, Davies S et al. A ran-domized comparison of off-pump and on-pump multivesselcoronary-artery bypass surgery. N Engl J Med 2004;350:21–28.

575. Smith SC Jr, Dove JT, Jacobs AK, Kennedy JW, Kereiakes D, Kern MJ et al.ACC/AHA guidelines of percutaneous coronary interventions (revision ofthe 1993 PTCA guidelines)–executive summary. A report of theAmerican College of Cardiology/American Heart Association TaskForce on Practice Guidelines (committee to revise the 1993 guidelinesfor percutaneous transluminal coronary angioplasty). J Am CollCardiol 2001;37:2215–2239.

576. Bucher HC, Hengstler P, Schindler C, Guyatt GH. Percutaneous translum-inal coronary angioplasty versus medical treatment for non-acute coron-ary heart disease: meta-analysis of randomised controlled trials. BMJ2000;321:73–77.

577. Parisi AF, Folland ED, Hartigan P. A comparison of angioplasty withmedical therapy in the treatment of single-vessel coronary arterydisease. Veterans Affairs ACME Investigators. N Engl J Med1992;326:10–16.

578. Folland ED, Hartigan PM, Parisi AF. Percutaneous transluminal coronaryangioplasty versus medical therapy for stable angina pectoris: outcomesfor patients with double-vessel versus single-vessel coronary arterydisease in a Veterans Affairs Cooperative randomized trial. VeteransAffairs ACME InvestigatorS. J Am Coll Cardiol 1997;29:1505–1511.

579. RITA-2 trial participants. Coronary angioplasty versus medical therapyfor angina: the second Randomised Intervention Treatment of Angina(RITA-2) trial participants. Lancet 1997;350:461–468.

580. Pitt B, Waters D, Brown WV, van Boven AJ, Schwartz L, Title LM et al.Aggressive lipid-lowering therapy compared with angioplasty in stablecoronary artery disease. Atorvastatin versus RevascularizationTreatment Investigators. N Engl J Med 1999;341:70–76.

581. Brophy JM, Belisle P, Joseph L. Evidence for use of coronary stents.A hierarchical bayesian meta-analysis. Ann Intern Med 2003;138:777–786.

582. Al Suwaidi J, Holmes DR Jr, Salam AM, Lennon R, Berger PB. Impact ofcoronary artery stents on mortality and nonfatal myocardial infarction:meta-analysis of randomized trials comparing a strategy of routinestenting with that of balloon angioplasty. Am Heart J 2004;147:815–822.

583. Morice MC, Serruys PW, Sousa JE, Fajadet J, Ban Hayashi E, Perin Met al. A randomized comparison of a sirolimus-eluting stent with a stan-dard stent for coronary revascularization. N Engl J Med2002;346:1773–1780.

584. Lansky AJ, Costa RA, Mintz GS, Tsuchiya Y, Midei M, Cox DA et al.Non-polymer-based paclitaxel-coated coronary stents for the treatmentof patients with de novo coronary lesions: angiographic follow-up of theDELIVER clinical trial. Circulation 2004;109:1948–1954.

585. Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O’ShaughnessyC et al. Sirolimus-eluting stents versus standard stents in patients withstenosis in a native coronary artery. N Engl J Med 2003;349:1315–1323.

586. Stone GW, Ellis SG, Cox DA, Hermiller J, O’Shaughnessy C, Mann JTet al.A polymer-based, paclitaxel-eluting stent in patients with coronaryartery disease. N Engl J Med 2004;350:221–231.

60 ESC Guidelines

587. Silber S, Albertsson P, Aviles FF, Camici PG, Colombo A, Hamm C et al.Guidelines for percutaneous coronary interventions. The Task Forcefor Percutaneous Coronary Interventions of the European Society ofCardiology. Eur Heart J 2005;26:804–847.

588. Pfisterer ME, Kiowski W, Brunner H, Burckhardt D, Burkart F. Long-termbenefit of 1-year amiodarone treatment for persistent complex ventri-cular arrhythmias after myocardial infarction. Circulation 1993;87:309–311.

589. Hueb WA, Bellotti G, de Oliveira SA, Arie S, de Albuquerque CP, JateneAD et al. The Medicine, Angioplasty or Surgery Study (MASS): a prospec-tive, randomized trial of medical therapy, balloon angioplasty or bypasssurgery for single proximal left anterior descending artery stenoses. JAm Coll Cardiol 1995;26:1600–1605.

590. The Bypass Angioplasty Revascularization Investigation (BARI)Investigators. Comparison of coronary bypass surgery with angioplastyin patients with multivessel disease. N Engl J Med 1996;335:217–225.

591. King SB III, Lembo NJ, Weintraub WS, Kosinski AS, Barnhart HX, Kutner MHet al. A randomized trial comparing coronary angioplasty with coronarybypass surgery. Emory Angioplasty versus Surgery Trial (EAST). N Engl JMed 1994;331:1044–1050.

592. Coronary angioplasty versus coronary artery bypass surgery: theRandomized Intervention Treatment of Angina (RITA) trial. Lancet1993;341:573–580.

593. Henderson RA, Pocock SJ, Sharp SJ, Nanchahal K, Sculpher MJ, Buxton MJet al. Long-term results of RITA-1 trial: clinical and cost comparisonsof coronary angioplasty and coronary-artery bypass grafting.Randomised Intervention Treatment of Angina. Lancet 1998;352:1419–1425.

594. Rodriguez A, Boullon F, Perez-Balino N, Paviotti C, Liprandi MI, PalaciosIF. Argentine randomized trial of percutaneous transluminal coronaryangioplasty versus coronary artery bypass surgery in multivesseldisease (ERACI): in-hospital results and 1-year follow-up. ERACI Group.J Am Coll Cardiol 1993;22:1060–1067.

595. Rodriguez A, Mele E, Peyregne E, Bullon F, Perez-Balino N, Liprandi MIet al. 3 year follow-up of the Argentine Randomized Trial ofPercutaneous Transluminal Coronary Angioplasty versus CoronaryArtery Bypass Surgery in Multivessel Disease (ERACI). J Am CollCardiol 1996;27:1178–1184.

596. CABRI Trial Participants. First-year results of CABRI (CoronaryAngioplasty versus Bypass Revascularisation Investigation). Lancet1995;346:1179–1184.

597. SoS Investigators. Coronary artery bypass surgery versus percutaneouscoronary intervention with stent implantation in patients with multives-sel coronary artery disease (the Stent or Surgery trial): a randomisedcontrolled trial. Lancet 2002;360:965–970.

598. Goy JJ, Kaufmann U, Goy-Eggenberger D, Garachemani A, Hurni M,Carrel T et al. A prospective randomized trial comparing stenting tointernal mammary artery grafting for proximal, isolated de novo leftanterior coronary artery stenosis: the SIMA trial. Stenting vs. InternalMammary Artery. Mayo Clin Proc 2000;75:1116–1123.

599. Pocock SJ, Henderson RA, Rickards AF, Hampton JR, King SB III, HammCW et al. Meta-analysis of randomised trials comparing coronary angio-plasty with bypass surgery. Lancet 1995;346:1184–1189.

600. Serruys PW, Unger F, Sousa JE, Jatene A, Bonnier HJ, Schonberger JPet al. Comparison of coronary-artery bypass surgery and stenting forthe treatment of multivessel disease. N Engl J Med2001;344:1117–1124.

601. Mercado N, Wijns W, Serruys PW, Sigwart U, Flather MD, Stables RHet al. 1 year outcomes of coronary artery bypass graft surgery versuspercutaneous coronary intervention with multiple stenting for multisys-tem disease: a meta-analysis of individual patient data from randomizedclinical trials. J Thorac Cardiovasc Surg 2005;130:512–519.

602. Hannan EL, Racz MJ, Walford G, Jones RH, Ryan TJ, Bennett E et al.Long-term outcomes of coronary-artery bypass grafting versus stentimplantation. N Engl J Med 2005;352:2174–2183.

603. Joyce D, Loebe M, Noon GP, McRee S, Southard R, Thompson L et al.Revascularization and ventricular restoration in patients with ischaemicheart failure: the STICH trial. Curr Opin Cardiol 2003;18:454–457.

604. Cleland JG, Freemantle N, Ball SG, Bonser RS, Camici P, Chattopadhyay Set al. The heart failure revascularisation trial (HEART): rationale, designand methodology. Eur J Heart Fail 2003;5:295–303.

605. Silvestri M, Barragan P, Sainsous J, Bayet G, Simeoni JB, Roquebert POet al. Unprotected left main coronary artery stenting: immediate andmedium-term outcomes of 140 elective procedures. J Am Coll Cardiol2000;35:1543–1550.

606. Black A, Cortina R, Bossi I, Choussat R, Fajadet J, Marco J. Unprotectedleft main coronary artery stenting: correlates of midterm survival andimpact of patient selection. J Am Coll Cardiol 2001;37:832–838.

607. Park SJ, Kim YH, Lee BK, Lee SW, Lee CW, Hong MK et al.Sirolimus-eluting stent implantation for unprotected left main coronaryartery stenosis: comparison with bare metal stent implantation. J AmColl Cardiol 2005;45:351–356.

608. Flaherty JD, Davidson CJ. Diabetes and coronary revascularization.JAMA 2005;293:1501–1508.

609. Brooks RC, Detre KM. Clinical trials of revascularization therapy in dia-betics. Curr Opin Cardiol 2000;15:287–292.

610. 7 year outcome in the Bypass Angioplasty RevascularizationInvestigation (BARI) by treatment and diabetic status. J Am CollCardiol 2000;35:1122–1129.

611. Schofer J, Schluter M, Gershlick AH, Wijns W, Garcia E, Schampaert Eet al. Sirolimus-eluting stents for treatment of patients with long ather-osclerotic lesions in small coronary arteries: double-blind, randomisedcontrolled trial (E-SIRIUS). Lancet 2003;362:1093–1099.

612. Lytle BW, Loop FD, Taylor PC, Simpfendorfer C, Kramer JR, Ratliff NBet al. Vein graft disease: the clinical impact of stenoses in saphenousvein bypass grafts to coronary arteries. J Thorac Cardiovasc Surg1992;103:831–840.

613. Lytle BW, Loop FD, Taylor PC, Goormastic M, Stewart RW, Novoa R et al.The effect of coronary reoperation on the survival of patients withstenoses in saphenous vein bypass grafts to coronary arteries. JThorac Cardiovasc Surg 1993;105:605–612; discussion 612–614.

614. Eagle KA, Guyton RA, Davidoff R, Edwards FH, Ewy GA, Gardner TJ et al.ACC/AHA 2004 guideline update for coronary artery bypass graftsurgery: summary article. A report of the American College ofCardiology/American Heart Association Task Force on PracticeGuidelines (Committee to Update the 1999 Guidelines for CoronaryArtery Bypass Graft Surgery). J Am Coll Cardiol 2004;44:1146–54–1213–310.

615. Baim DS, Wahr D, George B, Leon MB, Greenberg J, Cutlip DE et al.Randomized trial of a distal embolic protection device during percuta-neous intervention of saphenous vein aorto-coronary bypass grafts.Circulation 2002;105:1285–1290.

616. Sirnes PA, Golf S, Myreng Y, Molstad P, Emanuelsson H, Albertsson P et al.Stenting in Chronic Coronary Occlusion (SICCO): a randomized, con-trolled trial of adding stent implantation after successful angioplasty.J Am Coll Cardiol 1996;28:1444–1451.

617. Rubartelli P, Verna E, Niccoli L, Giachero C, Zimarino M, Bernardi Get al. Coronary stent implantation is superior to balloon angioplastyfor chronic coronary occlusions: 6 year clinical follow-up of theGISSOC trial. J Am Coll Cardiol 2003;41:1488–1492.

618. Dzavik V, Carere RG, Teo KK, Knudtson ML, Marquis JF, Buller CE. Anopen design, multicentre, randomized trial of percutaneous translum-inal coronary angioplasty versus stenting, with a heparin-coated stent,of totally occluded coronary arteries: rationale, trial design and base-line patient characteristics. Total Occlusion Study of Canada (TOSCA)Investigators. Can J Cardiol 1998;14:825–832.

619. Douglas PS, Ginsburg GS. The evaluation of chest pain in women. N EnglJ Med 1996;334:1311–1315.

620. Lerner DJ, Kannel WB. Patterns of coronary heart disease morbidity andmortality in the sexes: a 26-year follow-up of the Framingham popu-lation. Am Heart J 1986;111:383–390.

621. Campbell MJ, Elwood PC, Abbas S, Waters WE. Chest pain in women: astudy of prevalence and mortality follow up in south Wales. J EpidemiolCommunity Health 1984;38:17–20.

622. Shaper AG, Cook DG, Walker M, Macfarlane PW. Prevalence of ischaemicheart disease in middle aged British men. Br Heart J 1984;51:595–605.

623. Philpott S, Boynton PM, Feder G, Hemingway H. Gender differences indescriptions of angina symptoms and health problems immediatelyprior to angiography: the ACRE study. Appropriateness of CoronaryRevascularisation study. Soc Sci Med 2001;52:1565–1575.

624. Chaitman BR, Bourassa MG, Davis K, Rogers WJ, Tyras DH, Berger R et al.Angiographic prevalence of high-risk coronary artery disease in patientsubsets (CASS). Circulation 1981;64:360–367.

625. Villareal RPWJ. Noninvasive diagnostic testing. In: Wilansky SWJ, ed.Heart Disease in Women. Philadelphia: Churchill Livingstone; 2002.P149–157.

626. Osbakken MD, Okada RD, Boucher CA, Strauss HW, Pohost GM.Comparison of exercise perfusion and ventricular function imaging: ananalysis of factors affecting the diagnostic accuracy of each technique.J Am Coll Cardiol 1984;3:272–283.

ESC Guidelines 61

627. DePuey EG, Rozanski A. Using gated technetium-99m-sestamibi SPECTto characterize fixed myocardial defects as infarct or artifact. J NuclMed 1995;36:952–955.

628. Dodi C, Cortigiani L, Masini M, Olivotto I, Azzarelli A, Nannini E. Theincremental prognostic value of pharmacological stress echo over exer-cise electrocardiography in women with chest pain of unknown origin.Eur Heart J 2001;22:145–152.

629. Cortigiani L, Dodi C, Paolini EA, Bernardi D, Bruno G, Nannini E.Prognostic value of pharmacological stress echocardiography inwomen with chest pain and unknown coronary artery disease. J AmColl Cardiol 1998;32:1975–1981.

630. Melin JA, Wijns W, Vanbutsele RJ, Robert A, De Coster P, Brasseur LAet al. Alternative diagnostic strategies for coronary artery disease inwomen: demonstration of the usefulness and efficiency of probabilityanalysis. Circulation 1985;71:535–542.

631. Clarke KW, Gray D, Keating NA, Hampton JR. Do women with acute myo-cardial infarction receive the same treatment as men? BMJ1994;309:563–566.

632. Vaccarino V, Krumholz HM, Berkman LF, Horwitz RI. Sex differences inmortality after myocardial infarction. Is there evidence for an increasedrisk for women? Circulation 1995;91:1861–1871.

633. Vaccarino V, Krumholz HM, Yarzebski J, Gore JM, Goldberg RJ. Sexdifferences in 2-year mortality after hospital discharge for myocardialinfarction. Ann Intern Med 2001;134:173–181.

634. Roeters van Lennep JE, Zwinderman AH, Roeters van Lennep HW,Westerveld HE, Plokker HW, Voors AA et al. Gender differences in diag-nosis and treatment of coronary artery disease from 1981 to 1997. Noevidence for the Yentl syndrome. Eur Heart J 2000;21:911–918.

635. Daly CA, Clemens F, Sendon JL, Tavazzi L, Boersma E, Danchin N, Dela-haye F, Gitt A, Julian D, Mulcahy D, Ruzyllo W, Thygesen K, Verheugt F,Fox KM; Euro Heart Survey Investigators. Gender differences inthe management and clinical outcome of stable angina. Circulation2006;113:467–469.

636. Sowers JR. Diabetes in the elderly and in women: cardiovascular risks.Cardiol Clin 2004;22:541–551, vi.

637. McFarlane SI, Banerji M, Sowers JR. Insulin resistance and cardiovascu-lar disease. J Clin Endocrinol Metab 2001;86:713–718.

638. Blendea MC, McFarlane SI, Isenovic ER, Gick G, Sowers JR. Heart diseasein diabetic patients. Curr Diab Rep 2003;3:223–229.

639. Turner RC, Millns H, Neil HA, Stratton IM, Manley SE, Matthews DR et al.Risk factors for coronary artery disease in non-insulin dependent dia-betes mellitus: United Kingdom Prospective Diabetes Study (UKPDS:23). BMJ 1998;316:823–828.

640. Wei M, Gaskill SP, Haffner SM, Stern MP. Effects of diabetes and level ofglycemia on all-cause and cardiovascular mortality. The San AntonioHeart Study. Diabetes Care 1998;21:1167–1172.

641. Young LH, Jose P, Chyun D. Diagnosis of CAD in patients with diabetes:who to evaluate. Curr Diab Rep 2003;3:19–27.

642. Anand DV, Lim E, Lahiri A, Bax JJ. The role of non-invasive imaging inthe risk stratification of asymptomatic diabetic subjects. Eur Heart J.2005.

643. Giri S, Shaw LJ, Murthy DR, Travin MI, Miller DD, Hachamovitch R et al.Impact of diabetes on the risk stratification using stress single-photonemission computed tomography myocardial perfusion imaging inpatients with symptoms suggestive of coronary artery disease.Circulation 2002;105:32–40.

644. Fang ZY, Sharman J, Prins JB, Marwick TH. Determinants of exercisecapacity in patients with type 2 diabetes. Diabetes Care 2005;28:1643–1648.

645. The AACE System of intensive diabetes self-management-2002 update.The American Association of Clinical Endocrinologists MedicalGuidelines for the management of diabetes mellitus. Endocr PractSuppl 2002;8(Suppl.):40–82.

646. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucosecontrol with sulphonylureas or insulin compared with conventionaltreatment and risk of complications in patients with type 2 diabetes(UKPDS 33). Lancet 1998;352:837–853.

647. Hellman R, Regan J, Rosen H. Effect of intensive treatment of diabetesof the risk of death or renal failure in NIDDM and IDDM. Diabetes Care1997;20:258–264.

648. The American Association of Clinical Endocrinologists Medical Guidelinesfor the Management of Diabetes Mellitus: the AACE system of intensivediabetes self-management–2000 update. Endocr Pract 2000;6:43–84.

649. Standl E, Schnell O. A new look at the heart in diabetes mellitus: fromailing to failing. Diabetologia 2000;43:1455–1469.

650. Way KJ, Katai N, King GL. Protein kinase C and the development ofdiabetic vascular complications. Diabet Med 2001;18:945–959.

651. Lernfelt B, Landahl S, Svanborg A. Coronary heart disease at 70, 75 and79 years of age: a longitudinal study with special reference to sex differ-ences and mortality. Age Ageing 1990;19:297–303.

652. Kurita A, Takase B, Uehata A, Maruyama T, Nishioka T, Sugahara H et al.Painless myocardial ischemia in elderly patients compared withmiddle-aged patients and its relation to treadmill testing and coronaryhemodynamics. Clin Cardiol 1991;14:886–890.

653. Vasilomanolakis EC. Geriatric cardiology: when exercise stress testing isjustified. Geriatrics 1985;40:47–50–53–4, 57.

654. Kasser IS, Bruce RA.Comparative effects of aging and coronary heart diseaseon submaximal and maximal exercise. Circulation 1969;39:759–774.

655. Mehran R, Aymong ED, Nikolsky E, Lasic Z, Iakovou I, Fahy M et al. Asimple risk score for prediction of contrast-induced nephropathy afterpercutaneous coronary intervention: development and initial vali-dation. J Am Coll Cardiol 2004;44:1393–1399.

656. Montamat SC, Cusack BJ, Vestal RE. Management of drug therapy in theelderly. N Engl J Med 1989;321:303–309.

657. Gundersen T, Abrahamsen AM, Kjekshus J, Ronnevik PK. Timolol-relatedreduction in mortality and reinfarction in patients ages 65-75 yearssurviving acute myocardial infarction. Prepared for the NorwegianMulticentre Study Group. Circulation 1982;66:1179–1184.

658. Metzger JP, Tabone X, Georges JL, Gueniche C, Detienne JP, Le Feuvre Cet al. Coronary angioplasty in patients 75 years and older; comparisonwith coronary bypass surgery. Eur Heart J 1994;15:213–217.

659. Bonnier H, de Vries C, Michels R, el Gamal M. Initial and long-termresults of coronary angioplasty and coronary bypass surgery in patientsof 75 or older. Br Heart J 1993;70:122–125.

660. Mannheimer C, Camici P, Chester MR, Collins A, DeJongste M, Eliasson Tet al. The problem of chronic refractory angina; report from the ESCJoint Study Group on the Treatment of Refractory Angina. Eur Heart J2002;23:355–370.

661. Brorsson B, Bernstein SJ, Brook RH, Werko L. Quality of life of patientswith chronic stable angina before and 4 years after coronary revascular-isation compared with a normal population. Heart 2002;87:140–145.

662. Bernstein SJ, Brorsson B, Aberg T, Emanuelsson H, Brook RH, Werko L.Appropriateness of referral of coronary angiography patients inSweden. SECOR/SBU Project Group. Heart 1999;81:470–477.

663. Yang EH, Barsness GW, Gersh BJ, Chandrasekaran K, Lerman A. Currentand future treatment strategies for refractory angina. Mayo Clin Proc2004;79:1284–1292.

664. Faircloth ME, Redwood SR, Marber MS. Strategies for refractory angi-na–electric not eclectic? Int J Clin Pract 2004;58:650–652.

665. Kim MC, Kini A, Sharma SK. Refractory angina pectoris: mechanism andtherapeutic options. J Am Coll Cardiol 2002;39:923–934.

666. Arora RR, Chou TM, Jain D, Fleishman B, Crawford L, McKiernan T et al.The multicenter study of enhanced external counterpulsation(MUST-EECP): effect of EECP on exercise-induced myocardial ischemiaand anginal episodes. J Am Coll Cardiol 1999;33:1833–1840.

667. Soran O, Kennard ED, Kelsey SF, Holubkov R, Strobeck J, Feldman AM.Enhanced external counterpulsation as treatment for chronic anginain patients with left ventricular dysfunction: a report from theInternational EECP Patient Registry (IEPR). Congest Heart Fail2002;8:297–302.

668. Linnemeier G, Rutter MK, Barsness G, Kennard ED, Nesto RW. EnhancedExternal Counterpulsation for the relief of angina in patients with dia-betes: safety, efficacy and 1-year clinical outcomes. Am Heart J2003;146:453–458.

669. Allen KB, Dowling RD, Angell WW, Gangahar DM, Fudge TL, Richenbacher Wet al. Transmyocardial revascularization: 5-year follow-up of a prospective,randomized multicenter trial. Ann Thorac Surg 2004;77:1228–1234.

670. Schneider J, Diegeler A, Krakor R, Walther T, Kluge R, Mohr FW.Transmyocardial laser revascularization with the holmium:YAG laser:loss of symptomatic improvement after 2 years. Eur J CardiothoracSurg 2001;19:164–169.

671. Schofield PM, Sharples LD, Caine N, Burns S, Tait S, Wistow T et al.Transmyocardial laser revascularisation in patients with refractoryangina: a randomised controlled trial. Lancet 1999;353:519–524.

672. Leon MB, Kornowski R, Downey WE, Weisz G, Baim D, Bonow R,Hendel RC, Cohen D, Gervino E, Laham R, Lembo NJ, Moses JW, KuntzRE. A blinded, randomized, placebo-controlled trial of percutaneouslaser myocaridla revascularisation to improve angina symptoms inpatients with severe coronary disease. J Am Coll Cardiol 2005;46:1812–1819.

62 ESC Guidelines

673. Rimoldi O, Burns S, Rosen S, Wistow TE, Schofield PM, Taylor G, CamiciP. Measurement of myocardial blood flow with positorn eission tomogra-phy before and after transmyocardial laser revascularization.Circulation 1999;100(Suppl. II):II134–II138.

674. Daly CA, Clemens F, Sendon JL, Tavazzi L, Boersma E, Danchin N et al.The clinical characteristics and investigations planned in patients withstable angina presenting to cardiologists in Europe: from the EuroHeart Survey of Stable Angina. Eur Heart J 2005;26:996–1010.

675. Daly CA, Clemens F, Sendon JL, Tavazzi L, Boersma E, Danchin N et al.The initial management of stable angina in Europe, from the EuroHeart Survey: a description of pharmacological management and revas-cularization strategies initiated within the first month of presentation toa cardiologist in the Euro Heart Survey of Stable Angina. Eur Heart J2005;26:1011–1022.

676. Lopez-Sendon J, Swedberg K, McMurray J, Tamargo J, Maggioni AP,Dargie H et al. Expert consensus document on angiotensin convertingenzyme inhibitors in cardiovascular disease. The Task Force onACE-inhibitors of the European Society of Cardiology. Eur Heart J2004;25:1454–1470.

677. Lopez-Sendon J, Swedberg K, McMurray J, Tamargo J, Maggioni AP,Dargie H et al. Expert consensus document on beta-adrenergic receptorblockers. Eur Heart J 2004;25:1341–1362.

678. Mieres JH, Shaw LJ, Hendel RC, Miller DD, Bonow RO, Berman DS et al.American Society of Nuclear Cardiology consensus statement: Task

Force on Women and Coronary Artery Disease–the role of myocardialperfusion imaging in the clinical evaluation of coronary artery diseasein women [correction]. J Nucl Cardiol 2003;10:95–101.

679. Scanlon PJ, Faxon DP, Audet AM, Carabello B, Dehmer GJ, Eagle KAet al. ACC/AHA guidelines for coronary angiography. A report of theAmerican College of Cardiology/American Heart Association TaskForce on practice guidelines (Committee on Coronary Angiography).Developed in collaboration with the Society for Cardiac Angiographyand Interventions. J Am Coll Cardiol 1999;33:1756–1824.

680. Management of stable angina pectoris. Recommendations of the TaskForce of the European Society of Cardiology. Eur Heart J1997;18:394–413.

681. Weiner DA, Ryan TJ, Parsons L, Fisher LD, Chaitman BR, Sheffield LTet al. Long-term prognostic value of exercise testing in men andwomen from the Coronary Artery Surgery Study (CASS) registry. Am JCardiol 1995;75:865–870.

682. Alexander KP, Shaw LJ, Shaw LK, Delong ER, Mark DB, Peterson ED. Valueof exercise treadmill testing in women. J Am Coll Cardiol1998;32:1657–1664.

683. Goraya TY, Jacobsen SJ, Pellikka PA, Miller TD, Khan A, Weston SA et al.Prognostic value of treadmill exercise testing in elderly persons. AnnIntern Med 2000;132:862–870.

The CME Text ‘Guidelines on the Management of Stable Angina Pectoris’ is accredited by the European Board forAccreditation in Cardiology (EBAC) for ‘2’ hours of External CME credits. Each participant should claim only those hours ofcredit that have actually been spent in the educational activity. EBAC works according to the quality standards of theEuropean Accreditation Council for Continuing Medical Education (EACCME), which is an institution of the European Unionof Medical Specialists (UEMS).In compliance with EBAC/EACCME guidelines, all authors participating in this programme have disclosed potential conflicts

of interest that might cause a bias in the article. The Organizing Committee is responsible for ensuring that all potentialconflicts of interest relevant to the programme are declared to the participants prior to the CME activities.

ESC Guidelines 63